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McCall, Shannon Jones

Overview:

As an anatomic pathologist, I am involved in numerous translational cancer research projects that rely on the study of human biological samples.  I am the director of the Duke BioRepository & Precision Pathology Center, a shared resource of the School of Medicine and the Duke Cancer Institute.  My own area of research interest is gastrointestinal tract metaplasias and their relationship to carcinogenesis, particularly in the upper GI tract.

Positions:

Associate Professor of Pathology

Pathology
School of Medicine

Assistant Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1996

B.S. — North Carolina State University

M.D. 2000

M.D. — Duke University

Resident, Pathology

Duke University

News:

Grants:

Epigenomic Reprogramming in Patient Derived Models of Colorectal Cancer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2018
End Date
August 31, 2023

The role of gastrin in esophageal submucosal gland acinar ductal metaplasia

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Pathologist
Start Date
September 01, 2018
End Date
June 30, 2023

Mutation analysis of pap smear samples and associated tissues for ovarian cancer diagnostics

Administered By
Pathology
AwardedBy
Genendeavor LLC
Role
Principal Investigator
Start Date
October 12, 2017
End Date
October 11, 2022

Characterization of Tumor Immunobiological Factors that Promote Lymphovascular Invasion and Dissemination in Locally Advanced Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
August 15, 2017
End Date
August 14, 2020

Targeting differential apoptosis regulation in triple negative breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 30, 2016
End Date
September 29, 2019

Duke BRPC sub-contract with Leidos Biomed for NCI CPTAC III (Option1)

Administered By
Pathology
AwardedBy
Leidos Biomedical Research, Inc.
Role
Principal Investigator
Start Date
September 18, 2018
End Date
August 30, 2019

Preoperative Breast Radiotherapy: A Tool to Provide Individualized and Biologically-Based Radiation Therapy

Administered By
Radiation Oncology
AwardedBy
Gateway for Cancer Research
Role
Pathologist
Start Date
July 01, 2015
End Date
May 07, 2019

Rapid X-ray diffraction imaging for improved tissue analysis in pathologic applications

Administered By
Radiology
AwardedBy
North Carolina Biotechnology Center
Role
Collaborator
Start Date
November 01, 2017
End Date
April 30, 2019

ROCHE DIAGNOSTICS CORPORATION WORKFLOW ANALYSIS AGREEMENT

Administered By
Pathology
AwardedBy
Roche Diagnostics
Role
Principal Investigator
Start Date
March 26, 2018
End Date
March 25, 2019

Empowering Duke's Precision Pathology Center with Quantitative Image Analysis to Support Discovery, Diagnostic Assay Development, and Immune Cell Monitoring

Administered By
Pathology
AwardedBy
North Carolina Biotechnology Center
Role
Principal Investigator
Start Date
February 01, 2018
End Date
January 31, 2019

Lung Squamous Cell Carcinoma: Validation of Molecular Signatures of Prognosis

Administered By
Surgery, Cardiovascular and Thoracic Surgery
AwardedBy
University of Colorado - Denver
Role
Pathologist
Start Date
July 09, 2012
End Date
May 30, 2017

The genetics of hepatosplenic T cell lymphoma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2015
End Date
March 31, 2017

The effect of pre-analytical variables on the ability to detect PD-L1 by immunohistochemical staining of placental tissu

Administered By
Pathology
AwardedBy
Merck
Role
Principal Investigator
Start Date
November 05, 2014
End Date
January 18, 2015

TCGA Contract

Administered By
Pathology
AwardedBy
SAIC-Frederick, Inc.
Role
Principal Investigator
Start Date
December 03, 2013
End Date
December 31, 2014
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Awards:

Fellowship, Duke Clinical Leadership Program. Chancellor of Duke Medicine.

Type
School
Awarded By
Chancellor of Duke Medicine
Date
January 01, 2016

Bernard Fetter Faculty Teaching Award. Department of Pathology.

Type
Department
Awarded By
Department of Pathology
Date
January 01, 2015

William D. Bradford Resident Teaching Award. Department of Pathology.

Type
Department
Awarded By
Department of Pathology
Date
January 01, 2005

Alpha Omega Alpha, Medical Honor Society Induction. Alpha Omega Alpha.

Type
National
Awarded By
Alpha Omega Alpha
Date
January 01, 2004

Young Leader Award. College of American Pathologists.

Type
National
Awarded By
College of American Pathologists
Date
January 01, 2004

Tau Beta Pi Engineering Honor Society Induction. Tau Beta Pi.

Type
National
Awarded By
Tau Beta Pi
Date
January 01, 1994

Publications:

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

Authors
Korkut, A; Zaidi, S; Kanchi, RS; Rao, S; Gough, NR; Schultz, A; Li, X; Lorenzi, PL; Berger, AC; Robertson, G; Kwong, LN; Datto, M; Roszik, J; Ling, S; Ravikumar, V; Manyam, G; Rao, A; Shelley, S; Liu, Y; Ju, Z; Hansel, D; de Velasco, G; Pennathur, A; Andersen, JB; O'Rourke, CJ; Ohshiro, K; Jogunoori, W; Nguyen, B-N; Li, S; Osmanbeyoglu, HU; Ajani, JA; Mani, SA; Houseman, A; Wiznerowicz, M; Chen, J; Gu, S; Ma, W; Zhang, J; Tong, P; Cherniack, AD; Deng, C; Resar, L; Cancer Genome Atlas Research Network, ; Weinstein, JN; Mishra, L; Akbani, R
MLA Citation
Korkut, A, Zaidi, S, Kanchi, RS, Rao, S, Gough, NR, Schultz, A, Li, X, Lorenzi, PL, Berger, AC, Robertson, G, Kwong, LN, Datto, M, Roszik, J, Ling, S, Ravikumar, V, Manyam, G, Rao, A, Shelley, S, Liu, Y, Ju, Z, Hansel, D, de Velasco, G, Pennathur, A, Andersen, JB, O'Rourke, CJ, Ohshiro, K, Jogunoori, W, Nguyen, B-N, Li, S, Osmanbeyoglu, HU, Ajani, JA, Mani, SA, Houseman, A, Wiznerowicz, M, Chen, J, Gu, S, Ma, W, Zhang, J, Tong, P, Cherniack, AD, Deng, C, Resar, L, Cancer Genome Atlas Research Network, , Weinstein, JN, Mishra, L, and Akbani, R. "A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily." Cell Systems 7.4 (October 2018): 422-437.e7.
PMID
30268436
Source
epmc
Published In
Cell Systems
Volume
7
Issue
4
Publish Date
2018
Start Page
422
End Page
437.e7
DOI
10.1016/j.cels.2018.08.010

Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer.

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.

Authors
Wang, Y; Xu, X; Maglic, D; Dill, MT; Mojumdar, K; Ng, PK-S; Jeong, KJ; Tsang, YH; Moreno, D; Bhavana, VH; Peng, X; Ge, Z; Chen, H; Li, J; Chen, Z; Zhang, H; Han, L; Du, D; Creighton, CJ; Mills, GB; Cancer Genome Atlas Research Network, ; Camargo, F; Liang, H
MLA Citation
Wang, Y, Xu, X, Maglic, D, Dill, MT, Mojumdar, K, Ng, PK-S, Jeong, KJ, Tsang, YH, Moreno, D, Bhavana, VH, Peng, X, Ge, Z, Chen, H, Li, J, Chen, Z, Zhang, H, Han, L, Du, D, Creighton, CJ, Mills, GB, Cancer Genome Atlas Research Network, , Camargo, F, and Liang, H. "Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer." Cell Reports 25.5 (October 2018): 1304-1317.e5.
PMID
30380420
Source
epmc
Published In
Cell Reports
Volume
25
Issue
5
Publish Date
2018
Start Page
1304
End Page
1317.e5
DOI
10.1016/j.celrep.2018.10.001

Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients

© 2018 Elsevier Inc. Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions (“neojunctions”) in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders (“putative neoantigens”). A pan-cancer analysis by Kahles et al. shows increased alternative splicing events in tumors versus normal tissue and identifies trans-acting variants associated with alternative splicing events. Tumors contain neojunction-derived peptides absent in normal samples, including predicted MHC-I binders that are putative neoantigens.

Authors
Kahles, A; Lehmann, KV; Toussaint, NC; Hüser, M; Stark, SG; Sachsenberg, T; Stegle, O; Kohlbacher, O; Sander, C; Caesar-Johnson, SJ; Demchok, JA; Felau, I; Kasapi, M; Ferguson, ML; Hutter, CM; Sofia, HJ; Tarnuzzer, R; Wang, Z; Yang, L; Zenklusen, JC; Zhang, J; Chudamani, S; Liu, J; Lolla, L; Naresh, R; Pihl, T; Sun, Q; Wan, Y; Wu, Y; Cho, J; DeFreitas, T; Frazer, S; Gehlenborg, N; Getz, G; Heiman, DI; Kim, J; Lawrence, MS; Lin, P; Meier, S; Noble, MS; Saksena, G; Voet, D; Zhang, H; Bernard, B; Chambwe, N; Dhankani, V; Knijnenburg, T; Kramer, R; Leinonen, K; Liu, Y; Miller, M; Reynolds, S; Shmulevich, I; Thorsson, V; Zhang, W; Akbani, R; Broom, BM; Hegde, AM; Ju, Z; Kanchi, RS; Korkut, A; Li, J; Liang, H; Ling, S; Liu, W; Lu, Y; Mills, GB; Ng, KS; Rao, A; Ryan, M; Wang, J; Weinstein, JN; Abeshouse, A; Armenia, J; Chakravarty, D; Chatila, WK; de Bruijn, I; Gao, J; Gross, BE; Heins, ZJ; Kundra, R; La, K
MLA Citation
Kahles, A, Lehmann, KV, Toussaint, NC, Hüser, M, Stark, SG, Sachsenberg, T, Stegle, O, Kohlbacher, O, Sander, C, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, J, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Kim, J, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, Zhang, H, Bernard, B, Chambwe, N, Dhankani, V, Knijnenburg, T, Kramer, R, Leinonen, K, Liu, Y, Miller, M, Reynolds, S, Shmulevich, I, Thorsson, V, Zhang, W, Akbani, R, Broom, BM, Hegde, AM, Ju, Z, Kanchi, RS, Korkut, A, Li, J, Liang, H, Ling, S, Liu, W, Lu, Y, Mills, GB, Ng, KS, Rao, A, Ryan, M, Wang, J, Weinstein, JN, Abeshouse, A, Armenia, J, Chakravarty, D, Chatila, WK, de Bruijn, I, Gao, J, Gross, BE, Heins, ZJ, Kundra, R, and La, K. "Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients." Cancer Cell 34.2 (August 13, 2018): 211-224.e6.
Source
scopus
Published In
Cancer Cell
Volume
34
Issue
2
Publish Date
2018
Start Page
211
End Page
224.e6
DOI
10.1016/j.ccell.2018.07.001

Erratum: Comprehensive Characterization of Cancer Driver Genes and Mutations (ARTICLE (2018) 173(2) (371–385), (S009286741830237X), (10.1016/j.cell.2018.02.060))

© 2018 (Cell 173, 371–385.e1–e9; April 5, 2018) It has come to our attention that we made two errors in preparation of this manuscript. First, in the STAR Methods, under the subheading of “Hypermutators and Immune Infiltrates” within the “Quantification and Statistical Analysis” section, we inadvertently referred to Figures S7A–S7C for data corresponding to sample stratification by hypermutator status alone in the last sentence. It should have referred to Figure S6A–S6C. Second, the lists of highly frequent missense mutations for COAD (colon adenocarcinoma) and READ (rectum adenocarcinoma) displayed in Figure S7 were incorrect because when we ordered the mutations in the initial analysis, we mistakenly combined the two cancer types COAD and READ for analysis, despite the fact that they were listed as two separate cancer types in the x-axis of the figure. After re-ordering the mutations by frequency for COAD and READ independently, information on highly frequent missense mutations for each of these cancer types is different and updated now in the revised Figure S7. These errors don't change the major conclusions of the paper and have been corrected online. We apologize for any confusion they may have caused. [Figure-presented]

Authors
Bailey, MH; Tokheim, C; Porta-Pardo, E; Sengupta, S; Bertrand, D; Weerasinghe, A; Colaprico, A; Wendl, MC; Kim, J; Reardon, B; Kwok-Shing Ng, P; Jeong, KJ; Cao, S; Wang, Z; Gao, J; Gao, Q; Wang, F; Liu, EM; Mularoni, L; Rubio-Perez, C; Nagarajan, N; Cortés-Ciriano, I; Zhou, DC; Liang, WW; Hess, JM; Yellapantula, VD; Tamborero, D; Gonzalez-Perez, A; Suphavilai, C; Ko, JY; Khurana, E; Park, PJ; Van Allen, EM; Liang, H; Caesar-Johnson, SJ; Demchok, JA; Felau, I; Kasapi, M; Ferguson, ML; Hutter, CM; Sofia, HJ; Tarnuzzer, R; Yang, L; Zenklusen, JC; Zhang, J; Chudamani, S; Liu, J; Lolla, L; Naresh, R; Pihl, T; Sun, Q; Wan, Y; Wu, Y; Cho, J; DeFreitas, T; Frazer, S; Gehlenborg, N; Getz, G; Heiman, DI; Lawrence, MS; Lin, P; Meier, S; Noble, MS; Saksena, G; Voet, D; Zhang, H; Bernard, B; Chambwe, N; Dhankani, V; Knijnenburg, T; Kramer, R; Leinonen, K; Liu, Y; Miller, M; Reynolds, S; Shmulevich, I; Thorsson, V; Zhang, W; Akbani, R; Broom, BM; Hegde, AM; Ju, Z; Kanchi, RS; Korkut, A; Li, J; Ling, S; Liu, W; Lu, Y; Mills, GB; Ng, KS; Rao, A; Ryan, M; Wang, J; Weinstein, JN; Abeshouse, A; Armenia, J
MLA Citation
Bailey, MH, Tokheim, C, Porta-Pardo, E, Sengupta, S, Bertrand, D, Weerasinghe, A, Colaprico, A, Wendl, MC, Kim, J, Reardon, B, Kwok-Shing Ng, P, Jeong, KJ, Cao, S, Wang, Z, Gao, J, Gao, Q, Wang, F, Liu, EM, Mularoni, L, Rubio-Perez, C, Nagarajan, N, Cortés-Ciriano, I, Zhou, DC, Liang, WW, Hess, JM, Yellapantula, VD, Tamborero, D, Gonzalez-Perez, A, Suphavilai, C, Ko, JY, Khurana, E, Park, PJ, Van Allen, EM, Liang, H, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Yang, L, Zenklusen, JC, Zhang, J, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, Zhang, H, Bernard, B, Chambwe, N, Dhankani, V, Knijnenburg, T, Kramer, R, Leinonen, K, Liu, Y, Miller, M, Reynolds, S, Shmulevich, I, Thorsson, V, Zhang, W, Akbani, R, Broom, BM, Hegde, AM, Ju, Z, Kanchi, RS, Korkut, A, Li, J, Ling, S, Liu, W, Lu, Y, Mills, GB, Ng, KS, Rao, A, Ryan, M, Wang, J, Weinstein, JN, Abeshouse, A, and Armenia, J. "Erratum: Comprehensive Characterization of Cancer Driver Genes and Mutations (ARTICLE (2018) 173(2) (371–385), (S009286741830237X), (10.1016/j.cell.2018.02.060))." Cell 174.4 (August 9, 2018): 1034-1035.
Source
scopus
Published In
Cell
Volume
174
Issue
4
Publish Date
2018
Start Page
1034
End Page
1035
DOI
10.1016/j.cell.2018.07.034

Establishment of African American prostate cancer patient-derived primary cell lines and xenografts.

Authors
Patierno, B; Glover, W; Ribar, T; Kittles, R; Foo, W-C; McCall, S; Huang, J; George, D; Freedman, J; Patierno, S; Wood, K; Hsu, D
MLA Citation
Patierno, B, Glover, W, Ribar, T, Kittles, R, Foo, W-C, McCall, S, Huang, J, George, D, Freedman, J, Patierno, S, Wood, K, and Hsu, D. "Establishment of African American prostate cancer patient-derived primary cell lines and xenografts." 10th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved. September 25, 2017 - September 28, 2017. Atlanta, GA.: AMER ASSOC CANCER RESEARCH, July 1, 2018.
Source
wos
Published In
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
Volume
27
Issue
7
Publish Date
2018
Start Page
96
End Page
96

Esophageal submucosal glands as a potential source of subsquamous intestinal metaplasia in Barrett's esophagus.

Authors
Garman, KS; McCall, SJ
MLA Citation
Garman, KS, and McCall, SJ. "Esophageal submucosal glands as a potential source of subsquamous intestinal metaplasia in Barrett's esophagus." Gastrointestinal Endoscopy 88.1 (July 2018): 200-201. (Letter)
PMID
29935616
Source
epmc
Published In
Gastrointestinal Endoscopy
Volume
88
Issue
1
Publish Date
2018
Start Page
200
End Page
201
DOI
10.1016/j.gie.2018.01.027

Smarter Cancer Detection Through Machine-Learning Applied to High-Resolution Diffraction Tissue Scanning

Authors
Nacouzi, D; Spencer, J; Zhao, B; Leung, C; McCall, S; Greenberg, J; Kapadia, A
MLA Citation
Nacouzi, D, Spencer, J, Zhao, B, Leung, C, McCall, S, Greenberg, J, and Kapadia, A. "Smarter Cancer Detection Through Machine-Learning Applied to High-Resolution Diffraction Tissue Scanning." 60th Annual Meeting of the American-Association-of-Physicists-in-Medicine. July 29, 2018 - August 2, 2018. Nashville, TN.: WILEY, June 1, 2018.
Source
wos
Published In
Medical Physics
Volume
45
Issue
6
Publish Date
2018
Start Page
E503
End Page
E503

Smarter Cancer Detection Through Machine-Learning Applied to High-Resolution Diffraction Tissue Scanning

Authors
Nacouzi, D; Spencer, J; Zhao, B; Leung, C; McCall, S; Greenberg, J; Kapadia, A
MLA Citation
Nacouzi, D, Spencer, J, Zhao, B, Leung, C, McCall, S, Greenberg, J, and Kapadia, A. "Smarter Cancer Detection Through Machine-Learning Applied to High-Resolution Diffraction Tissue Scanning." 60th Annual Meeting of the American-Association-of-Physicists-in-Medicine. July 29, 2018 - August 2, 2018. Nashville, TN.: WILEY, June 1, 2018.
Source
wos
Published In
Medical Physics
Volume
45
Issue
6
Publish Date
2018
Start Page
E503
End Page
E503

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Authors
Ricketts, CJ; De Cubas, AA; Fan, H; Smith, CC; Lang, M; Reznik, E; Bowlby, R; Gibb, EA; Akbani, R; Beroukhim, R; Bottaro, DP; Choueiri, TK; Gibbs, RA; Godwin, AK; Haake, S; Hakimi, AA; Henske, EP; Hsieh, JJ; Ho, TH; Kanchi, RS; Krishnan, B; Kwiatkowski, DJ; Lui, W; Merino, MJ; Mills, GB; Myers, J; Nickerson, ML; Reuter, VE; Schmidt, LS; Shelley, CS; Shen, H; Shuch, B; Signoretti, S; Srinivasan, R; Tamboli, P; Thomas, G; Vincent, BG; Vocke, CD; Wheeler, DA; Yang, L; Kim, WY; Robertson, AG; Spellman, PT; Rathmell, WK; Linehan, WM; Caesar-Johnson, SJ; Demchok, JA; Felau, I; Kasapi, M; Ferguson, ML; Hutter, CM; Sofia, HJ; Tarnuzzer, R; Wang, Z; Yang, L; Zenklusen, JC; Zhang, JJ; Chudamani, S; Liu, J; Lolla, L; Naresh, R; Pihl, T; Sun, Q; Wan, Y; Wu, Y; Cho, J; DeFreitas, T; Frazer, S; Gehlenborg, N; Getz, G; Heiman, DI; Kim, J; Lawrence, MS; Lin, P; Meier, S; Noble, MS; Saksena, G; Voet, D; Zhang, H; Bernard, B; Chambwe, N; Dhankani, V; Knijnenburg, T; Kramer, R; Leinonen, K; Liu, Y; Miller, M; Reynolds, S; Shmulevich, I; Thorsson, V; Zhang, W; Broom, BM; Hegde, AM; Ju, Z; Korkut, A; Li, J; Liang, H; Ling, S; Liu, W; Lu, Y; Ng, K-S; Rao, A; Ryan, M; Wang, J; Weinstein, JN; Zhang, J; Abeshouse, A; Armenia, J; Chakravarty, D; Chatila, WK; de Bruijn, I; Gao, J; Gross, BE; Heins, ZJ; Kundra, R; La, K; Ladanyi, M; Luna, A; Nissan, MG; Ochoa, A; Phillips, SM; Sanchez-Vega, F; Sander, C; Schultz, N; Sheridan, R; Sumer, SO; Sun, Y; Taylor, BS; Wang, J; Zhang, H; Anur, P; Peto, M; Spellman, P; Benz, C; Stuart, JM; Wong, CK; Yau, C; Hayes, DN; Parker, JS; Wilkerson, MD; Ally, A; Balasundaram, M; Brooks, D; Carlsen, R; Chuah, E; Dhalla, N; Holt, R; Jones, SJM; Kasaian, K; Lee, D; Ma, Y; Marra, MA; Mayo, M; Moore, RA; Mungall, AJ; Mungall, K; Sadeghi, S; Schein, JE; Sipahimalani, P; Tam, A; Thiessen, N; Tse, K; Wong, T; Berger, AC; Cherniack, AD; Cibulskis, C; Gabriel, SB; Gao, GF; Ha, G; Meyerson, M; Schumacher, SE; Shih, J; Kucherlapati, MH; Kucherlapati, RS; Baylin, S; Cope, L; Danilova, L; Bootwalla, MS; Lai, PH; Maglinte, DT; Van Den Berg, DJ; Weisenberger, DJ; Auman, JT; Balu, S; Bodenheimer, T; Fan, C; Hoadley, KA; Hoyle, AP; Jefferys, SR; Jones, CD; Meng, S; Mieczkowski, PA; Mose, LE; Perou, AH; Perou, CM; Roach, J; Shi, Y; Simons, JV; Skelly, T; Soloway, MG; Tan, D; Veluvolu, U; Hinoue, T; Laird, PW; Zhou, W; Bellair, M; Chang, K; Covington, K; Creighton, CJ; Dinh, H; Doddapaneni, H; Donehower, LA; Drummond, J; Glenn, R; Hale, W; Han, Y; Hu, J; Korchina, V; Lee, S; Lewis, L; Li, W; Liu, X; Morgan, M; Morton, D; Muzny, D; Santibanez, J; Sheth, M; Shinbrot, E; Wang, L; Wang, M; Xi, L; Zhao, F; Hess, J; Appelbaum, EL; Bailey, M; Cordes, MG; Ding, L; Fronick, CC; Fulton, LA; Fulton, RS; Kandoth, C; Mardis, ER; McLellan, MD; Miller, CA; Schmidt, HK; Wilson, RK; Crain, D; Curley, E; Gardner, J; Lau, K; Mallery, D; Morris, S; Paulauskis, J; Penny, R; Shelton, C; Shelton, T; Sherman, M; Thompson, E; Yena, P; Bowen, J; Gastier-Foster, JM; Gerken, M; Leraas, KM; Lichtenberg, TM; Ramirez, NC; Wise, L; Zmuda, E; Corcoran, N; Costello, T; Hovens, C; Carvalho, AL; de Carvalho, AC; Fregnani, JH; Longatto-Filho, A; Reis, RM; Scapulatempo-Neto, C; Silveira, HCS; Vidal, DO; Burnette, A; Eschbacher, J; Hermes, B; Noss, A; Singh, R; Anderson, ML; Castro, PD; Ittmann, M; Huntsman, D; Kohl, B; Le, X; Thorp, R; Andry, C; Duffy, ER; Lyadov, V; Paklina, O; Setdikova, G; Shabunin, A; Tavobilov, M; McPherson, C; Warnick, R; Berkowitz, R; Cramer, D; Feltmate, C; Horowitz, N; Kibel, A; Muto, M; Raut, CP; Malykh, A; Barnholtz-Sloan, JS; Barrett, W; Devine, K; Fulop, J; Ostrom, QT; Shimmel, K; Wolinsky, Y; Sloan, AE; De Rose, A; Giuliante, F; Goodman, M; Karlan, BY; Hagedorn, CH; Eckman, J; Harr, J; Tucker, K; Zach, LA; Deyarmin, B; Hu, H; Kvecher, L; Larson, C; Mural, RJ; Somiari, S; Vicha, A; Zelinka, T; Bennett, J; Iacocca, M; Rabeno, B; Swanson, P; Latour, M; Lacombe, L; Têtu, B; Bergeron, A; McGraw, M; Staugaitis, SM; Chabot, J; Hibshoosh, H; Sepulveda, A; Su, T; Wang, T; Potapova, O; Voronina, O; Desjardins, L; Mariani, O; Roman-Roman, S; Sastre, X; Stern, M-H; Cheng, F; Berchuck, A; Bigner, D; Lipp, E; Marks, J; McCall, S; McLendon, R; Secord, A; Sharp, A; Behera, M; Brat, DJ; Chen, A; Delman, K; Force, S; Khuri, F; Magliocca, K; Maithel, S; Olson, JJ; Owonikoko, T; Pickens, A; Ramalingam, S; Shin, DM; Sica, G; Van Meir, EG; Zhang, H; Eijckenboom, W; Gillis, A; Korpershoek, E; Looijenga, L; Oosterhuis, W; Stoop, H; van Kessel, KE; Zwarthoff, EC; Calatozzolo, C; Cuppini, L; Cuzzubbo, S; DiMeco, F; Finocchiaro, G; Mattei, L; Perin, A; Pollo, B; Chen, C; Houck, J; Lohavanichbutr, P; Hartmann, A; Stoehr, C; Stoehr, R; Taubert, H; Wach, S; Wullich, B; Kycler, W; Murawa, D; Wiznerowicz, M; Chung, K; Edenfield, WJ; Martin, J; Baudin, E; Bubley, G; Bueno, R; De Rienzo, A; Richards, WG; Kalkanis, S; Mikkelsen, T; Noushmehr, H; Scarpace, L; Girard, N; Aymerich, M; Campo, E; Giné, E; Guillermo, AL; Van Bang, N; Hanh, PT; Phu, BD; Tang, Y; Colman, H; Evason, K; Dottino, PR; Martignetti, JA; Gabra, H; Juhl, H; Akeredolu, T; Stepa, S; Hoon, D; Ahn, K; Kang, KJ; Beuschlein, F; Breggia, A; Birrer, M; Bell, D; Borad, M; Bryce, AH; Castle, E; Chandan, V; Cheville, J; Copland, JA; Farnell, M; Flotte, T; Giama, N; Ho, T; Kendrick, M; Kocher, J-P; Kopp, K; Moser, C; Nagorney, D; O’Brien, D; O’Neill, BP; Patel, T; Petersen, G; Que, F; Rivera, M; Roberts, L; Smallridge, R; Smyrk, T; Stanton, M; Thompson, RH; Torbenson, M; Yang, JD; Zhang, L; Brimo, F; Ajani, JA; Gonzalez, AMA; Behrens, C; Bondaruk, J; Broaddus, R; Czerniak, B; Esmaeli, B; Fujimoto, J; Gershenwald, J; Guo, C; Lazar, AJ; Logothetis, C; Meric-Bernstam, F; Moran, C; Ramondetta, L; Rice, D; Sood, A; Thompson, T; Troncoso, P; Tsao, A; Wistuba, I; Carter, C; Haydu, L; Hersey, P; Jakrot, V; Kakavand, H; Kefford, R et al.
MLA Citation
Ricketts, CJ, De Cubas, AA, Fan, H, Smith, CC, Lang, M, Reznik, E, Bowlby, R, Gibb, EA, Akbani, R, Beroukhim, R, Bottaro, DP, Choueiri, TK, Gibbs, RA, Godwin, AK, Haake, S, Hakimi, AA, Henske, EP, Hsieh, JJ, Ho, TH, Kanchi, RS, Krishnan, B, Kwiatkowski, DJ, Lui, W, Merino, MJ, Mills, GB, Myers, J, Nickerson, ML, Reuter, VE, Schmidt, LS, Shelley, CS, Shen, H, Shuch, B, Signoretti, S, Srinivasan, R, Tamboli, P, Thomas, G, Vincent, BG, Vocke, CD, Wheeler, DA, Yang, L, Kim, WY, Robertson, AG, Spellman, PT, Rathmell, WK, Linehan, WM, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, JJ, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Kim, J, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, Zhang, H, Bernard, B, Chambwe, N, Dhankani, V, Knijnenburg, T, Kramer, R, Leinonen, K, Liu, Y, Miller, M, Reynolds, S, Shmulevich, I, Thorsson, V, Zhang, W, Broom, BM, Hegde, AM, Ju, Z, Korkut, A, Li, J, Liang, H, Ling, S, Liu, W, Lu, Y, Ng, K-S, Rao, A, Ryan, M, Wang, J, Weinstein, JN, Zhang, J, Abeshouse, A, Armenia, J, Chakravarty, D, Chatila, WK, de Bruijn, I, Gao, J, Gross, BE, Heins, ZJ, Kundra, R, La, K, Ladanyi, M, Luna, A, Nissan, MG, Ochoa, A, Phillips, SM, Sanchez-Vega, F, Sander, C, Schultz, N, Sheridan, R, Sumer, SO, Sun, Y, Taylor, BS, Wang, J, Zhang, H, Anur, P, Peto, M, Spellman, P, Benz, C, Stuart, JM, Wong, CK, Yau, C, Hayes, DN, Parker, JS, Wilkerson, MD, Ally, A, Balasundaram, M, Brooks, D, Carlsen, R, Chuah, E, Dhalla, N, Holt, R, Jones, SJM, Kasaian, K, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, K, Sadeghi, S, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Tse, K, Wong, T, Berger, AC, Cherniack, AD, Cibulskis, C, Gabriel, SB, Gao, GF, Ha, G, Meyerson, M, Schumacher, SE, Shih, J, Kucherlapati, MH, Kucherlapati, RS, Baylin, S, Cope, L, Danilova, L, Bootwalla, MS, Lai, PH, Maglinte, DT, Van Den Berg, DJ, Weisenberger, DJ, Auman, JT, Balu, S, Bodenheimer, T, Fan, C, Hoadley, KA, Hoyle, AP, Jefferys, SR, Jones, CD, Meng, S, Mieczkowski, PA, Mose, LE, Perou, AH, Perou, CM, Roach, J, Shi, Y, Simons, JV, Skelly, T, Soloway, MG, Tan, D, Veluvolu, U, Hinoue, T, Laird, PW, Zhou, W, Bellair, M, Chang, K, Covington, K, Creighton, CJ, Dinh, H, Doddapaneni, H, Donehower, LA, Drummond, J, Glenn, R, Hale, W, Han, Y, Hu, J, Korchina, V, Lee, S, Lewis, L, Li, W, Liu, X, Morgan, M, Morton, D, Muzny, D, Santibanez, J, Sheth, M, Shinbrot, E, Wang, L, Wang, M, Xi, L, Zhao, F, Hess, J, Appelbaum, EL, Bailey, M, Cordes, MG, Ding, L, Fronick, CC, Fulton, LA, Fulton, RS, Kandoth, C, Mardis, ER, McLellan, MD, Miller, CA, Schmidt, HK, Wilson, RK, Crain, D, Curley, E, Gardner, J, Lau, K, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Sherman, M, Thompson, E, Yena, P, Bowen, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Corcoran, N, Costello, T, Hovens, C, Carvalho, AL, de Carvalho, AC, Fregnani, JH, Longatto-Filho, A, Reis, RM, Scapulatempo-Neto, C, Silveira, HCS, Vidal, DO, Burnette, A, Eschbacher, J, Hermes, B, Noss, A, Singh, R, Anderson, ML, Castro, PD, Ittmann, M, Huntsman, D, Kohl, B, Le, X, Thorp, R, Andry, C, Duffy, ER, Lyadov, V, Paklina, O, Setdikova, G, Shabunin, A, Tavobilov, M, McPherson, C, Warnick, R, Berkowitz, R, Cramer, D, Feltmate, C, Horowitz, N, Kibel, A, Muto, M, Raut, CP, Malykh, A, Barnholtz-Sloan, JS, Barrett, W, Devine, K, Fulop, J, Ostrom, QT, Shimmel, K, Wolinsky, Y, Sloan, AE, De Rose, A, Giuliante, F, Goodman, M, Karlan, BY, Hagedorn, CH, Eckman, J, Harr, J, Tucker, K, Zach, LA, Deyarmin, B, Hu, H, Kvecher, L, Larson, C, Mural, RJ, Somiari, S, Vicha, A, Zelinka, T, Bennett, J, Iacocca, M, Rabeno, B, Swanson, P, Latour, M, Lacombe, L, Têtu, B, Bergeron, A, McGraw, M, Staugaitis, SM, Chabot, J, Hibshoosh, H, Sepulveda, A, Su, T, Wang, T, Potapova, O, Voronina, O, Desjardins, L, Mariani, O, Roman-Roman, S, Sastre, X, Stern, M-H, Cheng, F, Berchuck, A, Bigner, D, Lipp, E, Marks, J, McCall, S, McLendon, R, Secord, A, Sharp, A, Behera, M, Brat, DJ, Chen, A, Delman, K, Force, S, Khuri, F, Magliocca, K, Maithel, S, Olson, JJ, Owonikoko, T, Pickens, A, Ramalingam, S, Shin, DM, Sica, G, Van Meir, EG, Zhang, H, Eijckenboom, W, Gillis, A, Korpershoek, E, Looijenga, L, Oosterhuis, W, Stoop, H, van Kessel, KE, Zwarthoff, EC, Calatozzolo, C, Cuppini, L, Cuzzubbo, S, DiMeco, F, Finocchiaro, G, Mattei, L, Perin, A, Pollo, B, Chen, C, Houck, J, Lohavanichbutr, P, Hartmann, A, Stoehr, C, Stoehr, R, Taubert, H, Wach, S, Wullich, B, Kycler, W, Murawa, D, Wiznerowicz, M, Chung, K, Edenfield, WJ, Martin, J, Baudin, E, Bubley, G, Bueno, R, De Rienzo, A, Richards, WG, Kalkanis, S, Mikkelsen, T, Noushmehr, H, Scarpace, L, Girard, N, Aymerich, M, Campo, E, Giné, E, Guillermo, AL, Van Bang, N, Hanh, PT, Phu, BD, Tang, Y, Colman, H, Evason, K, Dottino, PR, Martignetti, JA, Gabra, H, Juhl, H, Akeredolu, T, Stepa, S, Hoon, D, Ahn, K, Kang, KJ, Beuschlein, F, Breggia, A, Birrer, M, Bell, D, Borad, M, Bryce, AH, Castle, E, Chandan, V, Cheville, J, Copland, JA, Farnell, M, Flotte, T, Giama, N, Ho, T, Kendrick, M, Kocher, J-P, Kopp, K, Moser, C, Nagorney, D, O’Brien, D, O’Neill, BP, Patel, T, Petersen, G, Que, F, Rivera, M, Roberts, L, Smallridge, R, Smyrk, T, Stanton, M, Thompson, RH, Torbenson, M, Yang, JD, Zhang, L, Brimo, F, Ajani, JA, Gonzalez, AMA, Behrens, C, Bondaruk, J, Broaddus, R, Czerniak, B, Esmaeli, B, Fujimoto, J, Gershenwald, J, Guo, C, Lazar, AJ, Logothetis, C, Meric-Bernstam, F, Moran, C, Ramondetta, L, Rice, D, Sood, A, Thompson, T, Troncoso, P, Tsao, A, Wistuba, I, Carter, C, Haydu, L, Hersey, P, Jakrot, V, Kakavand, H, and Kefford, R et al.. "The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma." Cell Reports 23.12 (June 2018): 3698-3698.
Source
crossref
Published In
Cell Reports
Volume
23
Issue
12
Publish Date
2018
Start Page
3698
End Page
3698
DOI
10.1016/j.celrep.2018.06.032

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

Authors
Siena, S; Sartore-Bianchi, A; Marsoni, S; Hurwitz, HI; McCall, SJ; Penault-Llorca, F; Srock, S; Bardelli, A; Trusolino, L
MLA Citation
Siena, S, Sartore-Bianchi, A, Marsoni, S, Hurwitz, HI, McCall, SJ, Penault-Llorca, F, Srock, S, Bardelli, A, and Trusolino, L. "Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer." Annals of Oncology : Official Journal of the European Society for Medical Oncology 29.5 (May 2018): 1108-1119.
PMID
29659677
Source
epmc
Published In
Annals of Oncology
Volume
29
Issue
5
Publish Date
2018
Start Page
1108
End Page
1119
DOI
10.1093/annonc/mdy100

The Immune Landscape of Cancer.

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

Authors
Thorsson, V; Gibbs, DL; Brown, SD; Wolf, D; Bortone, DS; Ou Yang, T-H; Porta-Pardo, E; Gao, GF; Plaisier, CL; Eddy, JA; Ziv, E; Culhane, AC; Paull, EO; Sivakumar, IKA; Gentles, AJ; Malhotra, R; Farshidfar, F; Colaprico, A; Parker, JS; Mose, LE; Vo, NS; Liu, J; Liu, Y; Rader, J; Dhankani, V; Reynolds, SM; Bowlby, R; Califano, A; Cherniack, AD; Anastassiou, D; Bedognetti, D; Rao, A; Chen, K; Krasnitz, A; Hu, H; Malta, TM; Noushmehr, H; Pedamallu, CS; Bullman, S; Ojesina, AI; Lamb, A; Zhou, W; Shen, H; Choueiri, TK; Weinstein, JN; Guinney, J; Saltz, J; Holt, RA; Rabkin, CE; Cancer Genome Atlas Research Network, ; Lazar, AJ; Serody, JS; Demicco, EG; Disis, ML; Vincent, BG; Shmulevich, L
MLA Citation
Thorsson, V, Gibbs, DL, Brown, SD, Wolf, D, Bortone, DS, Ou Yang, T-H, Porta-Pardo, E, Gao, GF, Plaisier, CL, Eddy, JA, Ziv, E, Culhane, AC, Paull, EO, Sivakumar, IKA, Gentles, AJ, Malhotra, R, Farshidfar, F, Colaprico, A, Parker, JS, Mose, LE, Vo, NS, Liu, J, Liu, Y, Rader, J, Dhankani, V, Reynolds, SM, Bowlby, R, Califano, A, Cherniack, AD, Anastassiou, D, Bedognetti, D, Rao, A, Chen, K, Krasnitz, A, Hu, H, Malta, TM, Noushmehr, H, Pedamallu, CS, Bullman, S, Ojesina, AI, Lamb, A, Zhou, W, Shen, H, Choueiri, TK, Weinstein, JN, Guinney, J, Saltz, J, Holt, RA, Rabkin, CE, Cancer Genome Atlas Research Network, , Lazar, AJ, Serody, JS, Demicco, EG, Disis, ML, Vincent, BG, and Shmulevich, L. "The Immune Landscape of Cancer." Immunity 48.4 (April 5, 2018): 812-830.e14.
PMID
29628290
Source
epmc
Published In
Immunity
Volume
48
Issue
4
Publish Date
2018
Start Page
812
End Page
830.e14
DOI
10.1016/j.immuni.2018.03.023

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

Authors
Liu, Y; Sethi, NS; Hinoue, T; Schneider, BG; Cherniack, AD; Sanchez-Vega, F; Seoane, JA; Farshidfar, F; Bowlby, R; Islam, M; Kim, J; Chatila, W; Akbani, R; Kanchi, RS; Rabkin, CS; Willis, JE; Wang, KK; McCall, SJ; Mishra, L; Ojesina, AI; Bullman, S; Pedamallu, CS; Lazar, AJ; Sakai, R; Cancer Genome Atlas Research Network, ; Thorsson, V; Bass, AJ; Laird, PW
MLA Citation
Liu, Y, Sethi, NS, Hinoue, T, Schneider, BG, Cherniack, AD, Sanchez-Vega, F, Seoane, JA, Farshidfar, F, Bowlby, R, Islam, M, Kim, J, Chatila, W, Akbani, R, Kanchi, RS, Rabkin, CS, Willis, JE, Wang, KK, McCall, SJ, Mishra, L, Ojesina, AI, Bullman, S, Pedamallu, CS, Lazar, AJ, Sakai, R, Cancer Genome Atlas Research Network, , Thorsson, V, Bass, AJ, and Laird, PW. "Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas." Cancer Cell 33.4 (April 2, 2018): 721-735.e8.
PMID
29622466
Source
epmc
Published In
Cancer Cell
Volume
33
Issue
4
Publish Date
2018
Start Page
721
End Page
735.e8
DOI
10.1016/j.ccell.2018.03.010

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer.

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

Authors
Wang, Z; Yang, B; Zhang, M; Guo, W; Wu, Z; Wang, Y; Jia, L; Li, S; Cancer Genome Atlas Research Network, ; Xie, W; Yang, D
MLA Citation
Wang, Z, Yang, B, Zhang, M, Guo, W, Wu, Z, Wang, Y, Jia, L, Li, S, Cancer Genome Atlas Research Network, , Xie, W, and Yang, D. "lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer." Cancer Cell 33.4 (April 2, 2018): 706-720.e9.
PMID
29622465
Source
epmc
Published In
Cancer Cell
Volume
33
Issue
4
Publish Date
2018
Start Page
706
End Page
720.e9
DOI
10.1016/j.ccell.2018.03.006

Genomic and Functional Approaches to Understanding Cancer Aneuploidy.

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

Authors
Taylor, AM; Shih, J; Ha, G; Gao, GF; Zhang, X; Berger, AC; Schumacher, SE; Wang, C; Hu, H; Liu, J; Lazar, AJ; Cancer Genome Atlas Research Network, ; Cherniack, AD; Beroukhim, R; Meyerson, M
MLA Citation
Taylor, AM, Shih, J, Ha, G, Gao, GF, Zhang, X, Berger, AC, Schumacher, SE, Wang, C, Hu, H, Liu, J, Lazar, AJ, Cancer Genome Atlas Research Network, , Cherniack, AD, Beroukhim, R, and Meyerson, M. "Genomic and Functional Approaches to Understanding Cancer Aneuploidy." Cancer Cell 33.4 (April 2, 2018): 676-689.e3.
PMID
29622463
Source
epmc
Published In
Cancer Cell
Volume
33
Issue
4
Publish Date
2018
Start Page
676
End Page
689.e3
DOI
10.1016/j.ccell.2018.03.007

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

Authors
Berger, AC; Korkut, A; Kanchi, RS; Hegde, AM; Lenoir, W; Liu, W; Liu, Y; Fan, H; Shen, H; Ravikumar, V; Rao, A; Schultz, A; Li, X; Sumazin, P; Williams, C; Mestdagh, P; Gunaratne, PH; Yau, C; Bowlby, R; Robertson, AG; Tiezzi, DG; Wang, C; Cherniack, AD; Godwin, AK; Kuderer, NM; Rader, JS; Zuna, RE; Sood, AK; Lazar, AJ; Ojesina, AI; Adebamowo, C; Adebamowo, SN; Baggerly, KA; Chen, T-W; Chiu, H-S; Lefever, S; Liu, L; MacKenzie, K; Orsulic, S; Roszik, J; Shelley, CS; Song, Q; Vellano, CP; Wentzensen, N; Cancer Genome Atlas Research Network, ; Weinstein, JN; Mills, GB; Levine, DA; Akbani, R
MLA Citation
Berger, AC, Korkut, A, Kanchi, RS, Hegde, AM, Lenoir, W, Liu, W, Liu, Y, Fan, H, Shen, H, Ravikumar, V, Rao, A, Schultz, A, Li, X, Sumazin, P, Williams, C, Mestdagh, P, Gunaratne, PH, Yau, C, Bowlby, R, Robertson, AG, Tiezzi, DG, Wang, C, Cherniack, AD, Godwin, AK, Kuderer, NM, Rader, JS, Zuna, RE, Sood, AK, Lazar, AJ, Ojesina, AI, Adebamowo, C, Adebamowo, SN, Baggerly, KA, Chen, T-W, Chiu, H-S, Lefever, S, Liu, L, MacKenzie, K, Orsulic, S, Roszik, J, Shelley, CS, Song, Q, Vellano, CP, Wentzensen, N, Cancer Genome Atlas Research Network, , Weinstein, JN, Mills, GB, Levine, DA, and Akbani, R. "A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers." Cancer Cell 33.4 (April 2, 2018): 690-705.e9.
PMID
29622464
Source
epmc
Published In
Cancer Cell
Volume
33
Issue
4
Publish Date
2018
Start Page
690
End Page
705.e9
DOI
10.1016/j.ccell.2018.03.014

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

Authors
Ricketts, CJ; De Cubas, AA; Fan, H; Smith, CC; Lang, M; Reznik, E; Bowlby, R; Gibb, EA; Akbani, R; Beroukhim, R; Bottaro, DP; Choueiri, TK; Gibbs, RA; Godwin, AK; Haake, S; Hakimi, AA; Henske, EP; Hsieh, JJ; Ho, TH; Kanchi, RS; Krishnan, B; Kwiatkowski, DJ; Lui, W; Merino, MJ; Mills, GB; Myers, J; Nickerson, ML; Reuter, VE; Schmidt, LS; Shelley, CS; Shen, H; Shuch, B; Signoretti, S; Srinivasan, R; Tamboli, P; Thomas, G; Vincent, BG; Vocke, CD; Wheeler, DA; Yang, L; Kim, WY; Robertson, AG; Cancer Genome Atlas Research Network, ; Spellman, PT; Rathmell, WK; Linehan, WM
MLA Citation
Ricketts, CJ, De Cubas, AA, Fan, H, Smith, CC, Lang, M, Reznik, E, Bowlby, R, Gibb, EA, Akbani, R, Beroukhim, R, Bottaro, DP, Choueiri, TK, Gibbs, RA, Godwin, AK, Haake, S, Hakimi, AA, Henske, EP, Hsieh, JJ, Ho, TH, Kanchi, RS, Krishnan, B, Kwiatkowski, DJ, Lui, W, Merino, MJ, Mills, GB, Myers, J, Nickerson, ML, Reuter, VE, Schmidt, LS, Shelley, CS, Shen, H, Shuch, B, Signoretti, S, Srinivasan, R, Tamboli, P, Thomas, G, Vincent, BG, Vocke, CD, Wheeler, DA, Yang, L, Kim, WY, Robertson, AG, Cancer Genome Atlas Research Network, , Spellman, PT, Rathmell, WK, and Linehan, WM. "The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma." Cell Reports 23.1 (April 2018): 313-326.e5.
PMID
29617669
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
313
End Page
326.e5
DOI
10.1016/j.celrep.2018.03.075

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context.

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts.

Authors
Chiu, H-S; Somvanshi, S; Patel, E; Chen, T-W; Singh, VP; Zorman, B; Patil, SL; Pan, Y; Chatterjee, SS; Cancer Genome Atlas Research Network, ; Sood, AK; Gunaratne, PH; Sumazin, P
MLA Citation
Chiu, H-S, Somvanshi, S, Patel, E, Chen, T-W, Singh, VP, Zorman, B, Patil, SL, Pan, Y, Chatterjee, SS, Cancer Genome Atlas Research Network, , Sood, AK, Gunaratne, PH, and Sumazin, P. "Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context." Cell Reports 23.1 (April 2018): 297-312.e12.
PMID
29617668
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
297
End Page
312.e12
DOI
10.1016/j.celrep.2018.03.064

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

Authors
Gao, Q; Liang, W-W; Foltz, SM; Mutharasu, G; Jayasinghe, RG; Cao, S; Liao, W-W; Reynolds, SM; Wyczalkowski, MA; Yao, L; Yu, L; Sun, SQ; Fusion Analysis Working Group, ; Cancer Genome Atlas Research Network, ; Chen, K; Lazar, AJ; Fields, RC; Wendl, MC; Van Tine, BA; Vij, R; Chen, F; Nykter, M; Shmulevich, I; Ding, L
MLA Citation
Gao, Q, Liang, W-W, Foltz, SM, Mutharasu, G, Jayasinghe, RG, Cao, S, Liao, W-W, Reynolds, SM, Wyczalkowski, MA, Yao, L, Yu, L, Sun, SQ, Fusion Analysis Working Group, , Cancer Genome Atlas Research Network, , Chen, K, Lazar, AJ, Fields, RC, Wendl, MC, Van Tine, BA, Vij, R, Chen, F, Nykter, M, Shmulevich, I, and Ding, L. "Driver Fusions and Their Implications in the Development and Treatment of Human Cancers." Cell Reports 23.1 (April 2018): 227-238.e3.
PMID
29617662
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
227
End Page
238.e3
DOI
10.1016/j.celrep.2018.03.050

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

Authors
Ding, L; Bailey, MH; Porta-Pardo, E; Thorsson, V; Colaprico, A; Bertrand, D; Gibbs, DL; Weerasinghe, A; Huang, K-L; Tokheim, C; Cortés-Ciriano, I; Jayasinghe, R; Chen, F; Yu, L; Sun, S; Olsen, C; Kim, J; Taylor, AM; Cherniack, AD; Akbani, R; Suphavilai, C; Nagarajan, N; Stuart, JM; Mills, GB; Wyczalkowski, MA; Vincent, BG; Hutter, CM; Zenklusen, JC; Hoadley, KA; Wendl, MC; Shmulevich, L; Lazar, AJ; Wheeler, DA; Getz, G; Cancer Genome Atlas Research Network,
MLA Citation
Ding, L, Bailey, MH, Porta-Pardo, E, Thorsson, V, Colaprico, A, Bertrand, D, Gibbs, DL, Weerasinghe, A, Huang, K-L, Tokheim, C, Cortés-Ciriano, I, Jayasinghe, R, Chen, F, Yu, L, Sun, S, Olsen, C, Kim, J, Taylor, AM, Cherniack, AD, Akbani, R, Suphavilai, C, Nagarajan, N, Stuart, JM, Mills, GB, Wyczalkowski, MA, Vincent, BG, Hutter, CM, Zenklusen, JC, Hoadley, KA, Wendl, MC, Shmulevich, L, Lazar, AJ, Wheeler, DA, Getz, G, and Cancer Genome Atlas Research Network, . "Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics." Cell 173.2 (April 2018): 305-320.e10.
PMID
29625049
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
305
End Page
320.e10
DOI
10.1016/j.cell.2018.03.033

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

Authors
Hoadley, KA; Yau, C; Hinoue, T; Wolf, DM; Lazar, AJ; Drill, E; Shen, R; Taylor, AM; Cherniack, AD; Thorsson, V; Akbani, R; Bowlby, R; Wong, CK; Wiznerowicz, M; Sanchez-Vega, F; Robertson, AG; Schneider, BG; Lawrence, MS; Noushmehr, H; Malta, TM; Cancer Genome Atlas Network, ; Stuart, JM; Benz, CC; Laird, PW
MLA Citation
Hoadley, KA, Yau, C, Hinoue, T, Wolf, DM, Lazar, AJ, Drill, E, Shen, R, Taylor, AM, Cherniack, AD, Thorsson, V, Akbani, R, Bowlby, R, Wong, CK, Wiznerowicz, M, Sanchez-Vega, F, Robertson, AG, Schneider, BG, Lawrence, MS, Noushmehr, H, Malta, TM, Cancer Genome Atlas Network, , Stuart, JM, Benz, CC, and Laird, PW. "Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer." Cell 173.2 (April 2018): 291-304.e6.
PMID
29625048
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
291
End Page
304.e6
DOI
10.1016/j.cell.2018.03.022

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images.

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment.

Authors
Saltz, J; Gupta, R; Hou, L; Kurc, T; Singh, P; Nguyen, V; Samaras, D; Shroyer, KR; Zhao, T; Batiste, R; Van Arnam, J; Cancer Genome Atlas Research Network, ; Shmulevich, I; Rao, AUK; Lazar, AJ; Sharma, A; Thorsson, V
MLA Citation
Saltz, J, Gupta, R, Hou, L, Kurc, T, Singh, P, Nguyen, V, Samaras, D, Shroyer, KR, Zhao, T, Batiste, R, Van Arnam, J, Cancer Genome Atlas Research Network, , Shmulevich, I, Rao, AUK, Lazar, AJ, Sharma, A, and Thorsson, V. "Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images." Cell Reports 23.1 (April 2018): 181-193.e7.
PMID
29617659
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
181
End Page
193.e7
DOI
10.1016/j.celrep.2018.03.086

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Authors
Huang, K-L; Mashl, RJ; Wu, Y; Ritter, DI; Wang, J; Oh, C; Paczkowska, M; Reynolds, S; Wyczalkowski, MA; Oak, N; Scott, AD; Krassowski, M; Cherniack, AD; Houlahan, KE; Jayasinghe, R; Wang, L-B; Zhou, DC; Liu, D; Cao, S; Kim, YW; Koire, A; McMichael, JF; Hucthagowder, V; Kim, T-B; Hahn, A; Wang, C; McLellan, MD; Al-Mulla, F; Johnson, KJ; Cancer Genome Atlas Research Network, ; Lichtarge, O; Boutros, PC; Raphael, B; Lazar, AJ; Zhang, W; Wendl, MC; Govindan, R; Jain, S; Wheeler, D; Kulkarni, S; Dipersio, JF; Reimand, J; Meric-Bernstam, F; Chen, K; Shmulevich, I; Plon, SE; Chen, F; Ding, L
MLA Citation
Huang, K-L, Mashl, RJ, Wu, Y, Ritter, DI, Wang, J, Oh, C, Paczkowska, M, Reynolds, S, Wyczalkowski, MA, Oak, N, Scott, AD, Krassowski, M, Cherniack, AD, Houlahan, KE, Jayasinghe, R, Wang, L-B, Zhou, DC, Liu, D, Cao, S, Kim, YW, Koire, A, McMichael, JF, Hucthagowder, V, Kim, T-B, Hahn, A, Wang, C, McLellan, MD, Al-Mulla, F, Johnson, KJ, Cancer Genome Atlas Research Network, , Lichtarge, O, Boutros, PC, Raphael, B, Lazar, AJ, Zhang, W, Wendl, MC, Govindan, R, Jain, S, Wheeler, D, Kulkarni, S, Dipersio, JF, Reimand, J, Meric-Bernstam, F, Chen, K, Shmulevich, I, Plon, SE, Chen, F, and Ding, L. "Pathogenic Germline Variants in 10,389 Adult Cancers." Cell 173.2 (April 2018): 355-370.e14.
PMID
29625052
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
355
End Page
370.e14
DOI
10.1016/j.cell.2018.03.039

Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

Authors
Peng, X; Chen, Z; Farshidfar, F; Xu, X; Lorenzi, PL; Wang, Y; Cheng, F; Tan, L; Mojumdar, K; Du, D; Ge, Z; Li, J; Thomas, GV; Birsoy, K; Liu, L; Zhang, H; Zhao, Z; Marchand, C; Weinstein, JN; Cancer Genome Atlas Research Network, ; Bathe, OF; Liang, H
MLA Citation
Peng, X, Chen, Z, Farshidfar, F, Xu, X, Lorenzi, PL, Wang, Y, Cheng, F, Tan, L, Mojumdar, K, Du, D, Ge, Z, Li, J, Thomas, GV, Birsoy, K, Liu, L, Zhang, H, Zhao, Z, Marchand, C, Weinstein, JN, Cancer Genome Atlas Research Network, , Bathe, OF, and Liang, H. "Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers." Cell Reports 23.1 (April 2018): 255-269.e4.
PMID
29617665
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
255
End Page
269.e4
DOI
10.1016/j.celrep.2018.03.077

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

Authors
Campbell, JD; Yau, C; Bowlby, R; Liu, Y; Brennan, K; Fan, H; Taylor, AM; Wang, C; Walter, V; Akbani, R; Byers, LA; Creighton, CJ; Coarfa, C; Shih, J; Cherniack, AD; Gevaert, O; Prunello, M; Shen, H; Anur, P; Chen, J; Cheng, H; Hayes, DN; Bullman, S; Pedamallu, CS; Ojesina, AI; Sadeghi, S; Mungall, KL; Robertson, AG; Benz, C; Schultz, A; Kanchi, RS; Gay, CM; Hegde, A; Diao, L; Wang, J; Ma, W; Sumazin, P; Chiu, H-S; Chen, T-W; Gunaratne, P; Donehower, L; Rader, JS; Zuna, R; Al-Ahmadie, H; Lazar, AJ; Flores, ER; Tsai, KY; Zhou, JH; Rustgi, AK; Drill, E; Shen, R; Wong, CK; Cancer Genome Atlas Research Network, ; Stuart, JM; Laird, PW; Hoadley, KA; Weinstein, JN; Peto, M; Pickering, CR; Chen, Z; Van Waes, C
MLA Citation
Campbell, JD, Yau, C, Bowlby, R, Liu, Y, Brennan, K, Fan, H, Taylor, AM, Wang, C, Walter, V, Akbani, R, Byers, LA, Creighton, CJ, Coarfa, C, Shih, J, Cherniack, AD, Gevaert, O, Prunello, M, Shen, H, Anur, P, Chen, J, Cheng, H, Hayes, DN, Bullman, S, Pedamallu, CS, Ojesina, AI, Sadeghi, S, Mungall, KL, Robertson, AG, Benz, C, Schultz, A, Kanchi, RS, Gay, CM, Hegde, A, Diao, L, Wang, J, Ma, W, Sumazin, P, Chiu, H-S, Chen, T-W, Gunaratne, P, Donehower, L, Rader, JS, Zuna, R, Al-Ahmadie, H, Lazar, AJ, Flores, ER, Tsai, KY, Zhou, JH, Rustgi, AK, Drill, E, Shen, R, Wong, CK, Cancer Genome Atlas Research Network, , Stuart, JM, Laird, PW, Hoadley, KA, Weinstein, JN, Peto, M, Pickering, CR, Chen, Z, and Van Waes, C. "Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas." Cell Reports 23.1 (April 2018): 194-212.e6.
PMID
29617660
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
194
End Page
212.e6
DOI
10.1016/j.celrep.2018.03.063

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.

Authors
Ge, Z; Leighton, JS; Wang, Y; Peng, X; Chen, Z; Chen, H; Sun, Y; Yao, F; Li, J; Zhang, H; Liu, J; Shriver, CD; Hu, H; Cancer Genome Atlas Research Network, ; Piwnica-Worms, H; Ma, L; Liang, H
MLA Citation
Ge, Z, Leighton, JS, Wang, Y, Peng, X, Chen, Z, Chen, H, Sun, Y, Yao, F, Li, J, Zhang, H, Liu, J, Shriver, CD, Hu, H, Cancer Genome Atlas Research Network, , Piwnica-Worms, H, Ma, L, and Liang, H. "Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types." Cell Reports 23.1 (April 2018): 213-226.e3.
PMID
29617661
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
213
End Page
226.e3
DOI
10.1016/j.celrep.2018.03.047

Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas.

Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders.

Authors
Way, GP; Sanchez-Vega, F; La, K; Armenia, J; Chatila, WK; Luna, A; Sander, C; Cherniack, AD; Mina, M; Ciriello, G; Schultz, N; Cancer Genome Atlas Research Network, ; Sanchez, Y; Greene, CS
MLA Citation
Way, GP, Sanchez-Vega, F, La, K, Armenia, J, Chatila, WK, Luna, A, Sander, C, Cherniack, AD, Mina, M, Ciriello, G, Schultz, N, Cancer Genome Atlas Research Network, , Sanchez, Y, and Greene, CS. "Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas." Cell Reports 23.1 (April 2018): 172-180.e3.
PMID
29617658
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
172
End Page
180.e3
DOI
10.1016/j.celrep.2018.03.046

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Authors
Chen, H; Li, C; Peng, X; Zhou, Z; Weinstein, JN; Liang, H; Caesar-Johnson, SJ; Demchok, JA; Felau, I; Kasapi, M; Ferguson, ML; Hutter, CM; Sofia, HJ; Tarnuzzer, R; Wang, Z; Yang, L; Zenklusen, JC; Zhang, JJ; Chudamani, S; Liu, J; Lolla, L; Naresh, R; Pihl, T; Sun, Q; Wan, Y; Wu, Y; Cho, J; DeFreitas, T; Frazer, S; Gehlenborg, N; Getz, G; Heiman, DI; Kim, J; Lawrence, MS; Lin, P; Meier, S; Noble, MS; Saksena, G; Voet, D; Zhang, H; Bernard, B; Chambwe, N; Dhankani, V; Knijnenburg, T; Kramer, R; Leinonen, K; Liu, Y; Miller, M; Reynolds, S; Shmulevich, I; Thorsson, V; Zhang, W; Akbani, R; Broom, BM; Hegde, AM; Ju, Z; Kanchi, RS; Korkut, A; Li, J; Ling, S; Liu, W; Lu, Y; Mills, GB; Ng, K-S; Rao, A; Ryan, M; Wang, J; Zhang, J; Abeshouse, A; Armenia, J; Chakravarty, D; Chatila, WK; de Bruijn, I; Gao, J; Gross, BE; Heins, ZJ; Kundra, R; La, K; Ladanyi, M; Luna, A; Nissan, MG; Ochoa, A; Phillips, SM; Reznik, E; Sanchez-Vega, F; Sander, C; Schultz, N; Sheridan, R; Sumer, SO; Sun, Y; Taylor, BS; Wang, J; Zhang, H; Anur, P; Peto, M; Spellman, P; Benz, C; Stuart, JM; Wong, CK; Yau, C; Hayes, DN; Parker, JS; Wilkerson, MD; Ally, A; Balasundaram, M; Bowlby, R; Brooks, D; Carlsen, R; Chuah, E; Dhalla, N; Holt, R; Jones, SJM; Kasaian, K; Lee, D; Ma, Y; Marra, MA; Mayo, M; Moore, RA; Mungall, AJ; Mungall, K; Robertson, AG; Sadeghi, S; Schein, JE; Sipahimalani, P; Tam, A; Thiessen, N; Tse, K; Wong, T; Berger, AC; Beroukhim, R; Cherniack, AD; Cibulskis, C; Gabriel, SB; Gao, GF; Ha, G; Meyerson, M; Schumacher, SE; Shih, J; Kucherlapati, MH; Kucherlapati, RS; Baylin, S; Cope, L; Danilova, L; Bootwalla, MS; Lai, PH; Maglinte, DT; Van Den Berg, DJ; Weisenberger, DJ; Auman, JT; Balu, S; Bodenheimer, T; Fan, C; Hoadley, KA; Hoyle, AP; Jefferys, SR; Jones, CD; Meng, S; Mieczkowski, PA; Mose, LE; Perou, AH; Perou, CM; Roach, J; Shi, Y; Simons, JV; Skelly, T; Soloway, MG; Tan, D; Veluvolu, U; Fan, H; Hinoue, T; Laird, PW; Shen, H; Zhou, W; Bellair, M; Chang, K; Covington, K; Creighton, CJ; Dinh, H; Doddapaneni, H; Donehower, LA; Drummond, J; Gibbs, RA; Glenn, R; Hale, W; Han, Y; Hu, J; Korchina, V; Lee, S; Lewis, L; Li, W; Liu, X; Morgan, M; Morton, D; Muzny, D; Santibanez, J; Sheth, M; Shinbrot, E; Wang, L; Wang, M; Wheeler, DA; Xi, L; Zhao, F; Hess, J; Appelbaum, EL; Bailey, M; Cordes, MG; Ding, L; Fronick, CC; Fulton, LA; Fulton, RS; Kandoth, C; Mardis, ER; McLellan, MD; Miller, CA; Schmidt, HK; Wilson, RK; Crain, D; Curley, E; Gardner, J; Lau, K; Mallery, D; Morris, S; Paulauskis, J; Penny, R; Shelton, C; Shelton, T; Sherman, M; Thompson, E; Yena, P; Bowen, J; Gastier-Foster, JM; Gerken, M; Leraas, KM; Lichtenberg, TM; Ramirez, NC; Wise, L; Zmuda, E; Corcoran, N; Costello, T; Hovens, C; Carvalho, AL; de Carvalho, AC; Fregnani, JH; Longatto-Filho, A; Reis, RM; Scapulatempo-Neto, C; Silveira, HCS; Vidal, DO; Burnette, A; Eschbacher, J; Hermes, B; Noss, A; Singh, R; Anderson, ML; Castro, PD; Ittmann, M; Huntsman, D; Kohl, B; Le, X; Thorp, R; Andry, C; Duffy, ER; Lyadov, V; Paklina, O; Setdikova, G; Shabunin, A; Tavobilov, M; McPherson, C; Warnick, R; Berkowitz, R; Cramer, D; Feltmate, C; Horowitz, N; Kibel, A; Muto, M; Raut, CP; Malykh, A; Barnholtz-Sloan, JS; Barrett, W; Devine, K; Fulop, J; Ostrom, QT; Shimmel, K; Wolinsky, Y; Sloan, AE; De Rose, A; Giuliante, F; Goodman, M; Karlan, BY; Hagedorn, CH; Eckman, J; Harr, J; Myers, J; Tucker, K; Zach, LA; Deyarmin, B; Hu, H; Kvecher, L; Larson, C; Mural, RJ; Somiari, S; Vicha, A; Zelinka, T; Bennett, J; Iacocca, M; Rabeno, B; Swanson, P; Latour, M; Lacombe, L; Têtu, B; Bergeron, A; McGraw, M; Staugaitis, SM; Chabot, J; Hibshoosh, H; Sepulveda, A; Su, T; Wang, T; Potapova, O; Voronina, O; Desjardins, L; Mariani, O; Roman-Roman, S; Sastre, X; Stern, M-H; Cheng, F; Signoretti, S; Berchuck, A; Bigner, D; Lipp, E; Marks, J; McCall, S; McLendon, R; Secord, A; Sharp, A; Behera, M; Brat, DJ; Chen, A; Delman, K; Force, S; Khuri, F; Magliocca, K; Maithel, S; Olson, JJ; Owonikoko, T; Pickens, A; Ramalingam, S; Shin, DM; Sica, G; Van Meir, EG; Zhang, H; Eijckenboom, W; Gillis, A; Korpershoek, E; Looijenga, L; Oosterhuis, W; Stoop, H; van Kessel, KE; Zwarthoff, EC; Calatozzolo, C; Cuppini, L; Cuzzubbo, S; DiMeco, F; Finocchiaro, G; Mattei, L; Perin, A; Pollo, B; Chen, C; Houck, J; Lohavanichbutr, P; Hartmann, A; Stoehr, C; Stoehr, R; Taubert, H; Wach, S; Wullich, B; Kycler, W; Murawa, D; Wiznerowicz, M; Chung, K; Edenfield, WJ; Martin, J; Baudin, E; Bubley, G; Bueno, R; De Rienzo, A; Richards, WG; Kalkanis, S; Mikkelsen, T; Noushmehr, H; Scarpace, L; Girard, N; Aymerich, M; Campo, E; Giné, E; Guillermo, AL; Van Bang, N; Hanh, PT; Phu, BD; Tang, Y; Colman, H; Evason, K; Dottino, PR; Martignetti, JA; Gabra, H; Juhl, H; Akeredolu, T; Stepa, S; Hoon, D; Ahn, K; Kang, KJ; Beuschlein, F; Breggia, A; Birrer, M; Bell, D; Borad, M; Bryce, AH; Castle, E; Chandan, V; Cheville, J; Copland, JA; Farnell, M; Flotte, T; Giama, N; Ho, T; Kendrick, M; Kocher, J-P; Kopp, K; Moser, C; Nagorney, D; O’Brien, D; O’Neill, BP; Patel, T; Petersen, G; Que, F; Rivera, M; Roberts, L; Smallridge, R; Smyrk, T; Stanton, M; Thompson, RH; Torbenson, M; Yang, JD; Zhang, L; Brimo, F; Ajani, JA; Gonzalez, AMA; Behrens, C; Bondaruk, J; Broaddus, R; Czerniak, B; Esmaeli, B; Fujimoto, J; Gershenwald, J; Guo, C; Lazar, AJ; Logothetis, C; Meric-Bernstam, F; Moran, C; Ramondetta, L; Rice, D; Sood, A; Tamboli, P; Thompson, T; Troncoso, P; Tsao, A; Wistuba, I; Carter, C; Haydu, L; Hersey, P; Jakrot, V; Kakavand, H; Kefford, R; Lee, K; Long, G; Mann, G; Quinn, M; Saw, R; Scolyer, R; Shannon, K; Spillane, A; Stretch, J; Synott, M; Thompson, J; Wilmott, J; Al-Ahmadie, H; Chan, TA; Ghossein, R; Gopalan, A; Levine, DA; Reuter, V; Singer, S; Singh, B; Tien, NV; Broudy, T; Mirsaidi, C; Nair, P; Drwiega, P; Miller, J; Smith, J et al.
MLA Citation
Chen, H, Li, C, Peng, X, Zhou, Z, Weinstein, JN, Liang, H, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, JJ, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Kim, J, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, Zhang, H, Bernard, B, Chambwe, N, Dhankani, V, Knijnenburg, T, Kramer, R, Leinonen, K, Liu, Y, Miller, M, Reynolds, S, Shmulevich, I, Thorsson, V, Zhang, W, Akbani, R, Broom, BM, Hegde, AM, Ju, Z, Kanchi, RS, Korkut, A, Li, J, Ling, S, Liu, W, Lu, Y, Mills, GB, Ng, K-S, Rao, A, Ryan, M, Wang, J, Zhang, J, Abeshouse, A, Armenia, J, Chakravarty, D, Chatila, WK, de Bruijn, I, Gao, J, Gross, BE, Heins, ZJ, Kundra, R, La, K, Ladanyi, M, Luna, A, Nissan, MG, Ochoa, A, Phillips, SM, Reznik, E, Sanchez-Vega, F, Sander, C, Schultz, N, Sheridan, R, Sumer, SO, Sun, Y, Taylor, BS, Wang, J, Zhang, H, Anur, P, Peto, M, Spellman, P, Benz, C, Stuart, JM, Wong, CK, Yau, C, Hayes, DN, Parker, JS, Wilkerson, MD, Ally, A, Balasundaram, M, Bowlby, R, Brooks, D, Carlsen, R, Chuah, E, Dhalla, N, Holt, R, Jones, SJM, Kasaian, K, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Mungall, K, Robertson, AG, Sadeghi, S, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Tse, K, Wong, T, Berger, AC, Beroukhim, R, Cherniack, AD, Cibulskis, C, Gabriel, SB, Gao, GF, Ha, G, Meyerson, M, Schumacher, SE, Shih, J, Kucherlapati, MH, Kucherlapati, RS, Baylin, S, Cope, L, Danilova, L, Bootwalla, MS, Lai, PH, Maglinte, DT, Van Den Berg, DJ, Weisenberger, DJ, Auman, JT, Balu, S, Bodenheimer, T, Fan, C, Hoadley, KA, Hoyle, AP, Jefferys, SR, Jones, CD, Meng, S, Mieczkowski, PA, Mose, LE, Perou, AH, Perou, CM, Roach, J, Shi, Y, Simons, JV, Skelly, T, Soloway, MG, Tan, D, Veluvolu, U, Fan, H, Hinoue, T, Laird, PW, Shen, H, Zhou, W, Bellair, M, Chang, K, Covington, K, Creighton, CJ, Dinh, H, Doddapaneni, H, Donehower, LA, Drummond, J, Gibbs, RA, Glenn, R, Hale, W, Han, Y, Hu, J, Korchina, V, Lee, S, Lewis, L, Li, W, Liu, X, Morgan, M, Morton, D, Muzny, D, Santibanez, J, Sheth, M, Shinbrot, E, Wang, L, Wang, M, Wheeler, DA, Xi, L, Zhao, F, Hess, J, Appelbaum, EL, Bailey, M, Cordes, MG, Ding, L, Fronick, CC, Fulton, LA, Fulton, RS, Kandoth, C, Mardis, ER, McLellan, MD, Miller, CA, Schmidt, HK, Wilson, RK, Crain, D, Curley, E, Gardner, J, Lau, K, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, C, Shelton, T, Sherman, M, Thompson, E, Yena, P, Bowen, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Corcoran, N, Costello, T, Hovens, C, Carvalho, AL, de Carvalho, AC, Fregnani, JH, Longatto-Filho, A, Reis, RM, Scapulatempo-Neto, C, Silveira, HCS, Vidal, DO, Burnette, A, Eschbacher, J, Hermes, B, Noss, A, Singh, R, Anderson, ML, Castro, PD, Ittmann, M, Huntsman, D, Kohl, B, Le, X, Thorp, R, Andry, C, Duffy, ER, Lyadov, V, Paklina, O, Setdikova, G, Shabunin, A, Tavobilov, M, McPherson, C, Warnick, R, Berkowitz, R, Cramer, D, Feltmate, C, Horowitz, N, Kibel, A, Muto, M, Raut, CP, Malykh, A, Barnholtz-Sloan, JS, Barrett, W, Devine, K, Fulop, J, Ostrom, QT, Shimmel, K, Wolinsky, Y, Sloan, AE, De Rose, A, Giuliante, F, Goodman, M, Karlan, BY, Hagedorn, CH, Eckman, J, Harr, J, Myers, J, Tucker, K, Zach, LA, Deyarmin, B, Hu, H, Kvecher, L, Larson, C, Mural, RJ, Somiari, S, Vicha, A, Zelinka, T, Bennett, J, Iacocca, M, Rabeno, B, Swanson, P, Latour, M, Lacombe, L, Têtu, B, Bergeron, A, McGraw, M, Staugaitis, SM, Chabot, J, Hibshoosh, H, Sepulveda, A, Su, T, Wang, T, Potapova, O, Voronina, O, Desjardins, L, Mariani, O, Roman-Roman, S, Sastre, X, Stern, M-H, Cheng, F, Signoretti, S, Berchuck, A, Bigner, D, Lipp, E, Marks, J, McCall, S, McLendon, R, Secord, A, Sharp, A, Behera, M, Brat, DJ, Chen, A, Delman, K, Force, S, Khuri, F, Magliocca, K, Maithel, S, Olson, JJ, Owonikoko, T, Pickens, A, Ramalingam, S, Shin, DM, Sica, G, Van Meir, EG, Zhang, H, Eijckenboom, W, Gillis, A, Korpershoek, E, Looijenga, L, Oosterhuis, W, Stoop, H, van Kessel, KE, Zwarthoff, EC, Calatozzolo, C, Cuppini, L, Cuzzubbo, S, DiMeco, F, Finocchiaro, G, Mattei, L, Perin, A, Pollo, B, Chen, C, Houck, J, Lohavanichbutr, P, Hartmann, A, Stoehr, C, Stoehr, R, Taubert, H, Wach, S, Wullich, B, Kycler, W, Murawa, D, Wiznerowicz, M, Chung, K, Edenfield, WJ, Martin, J, Baudin, E, Bubley, G, Bueno, R, De Rienzo, A, Richards, WG, Kalkanis, S, Mikkelsen, T, Noushmehr, H, Scarpace, L, Girard, N, Aymerich, M, Campo, E, Giné, E, Guillermo, AL, Van Bang, N, Hanh, PT, Phu, BD, Tang, Y, Colman, H, Evason, K, Dottino, PR, Martignetti, JA, Gabra, H, Juhl, H, Akeredolu, T, Stepa, S, Hoon, D, Ahn, K, Kang, KJ, Beuschlein, F, Breggia, A, Birrer, M, Bell, D, Borad, M, Bryce, AH, Castle, E, Chandan, V, Cheville, J, Copland, JA, Farnell, M, Flotte, T, Giama, N, Ho, T, Kendrick, M, Kocher, J-P, Kopp, K, Moser, C, Nagorney, D, O’Brien, D, O’Neill, BP, Patel, T, Petersen, G, Que, F, Rivera, M, Roberts, L, Smallridge, R, Smyrk, T, Stanton, M, Thompson, RH, Torbenson, M, Yang, JD, Zhang, L, Brimo, F, Ajani, JA, Gonzalez, AMA, Behrens, C, Bondaruk, J, Broaddus, R, Czerniak, B, Esmaeli, B, Fujimoto, J, Gershenwald, J, Guo, C, Lazar, AJ, Logothetis, C, Meric-Bernstam, F, Moran, C, Ramondetta, L, Rice, D, Sood, A, Tamboli, P, Thompson, T, Troncoso, P, Tsao, A, Wistuba, I, Carter, C, Haydu, L, Hersey, P, Jakrot, V, Kakavand, H, Kefford, R, Lee, K, Long, G, Mann, G, Quinn, M, Saw, R, Scolyer, R, Shannon, K, Spillane, A, Stretch, J, Synott, M, Thompson, J, Wilmott, J, Al-Ahmadie, H, Chan, TA, Ghossein, R, Gopalan, A, Levine, DA, Reuter, V, Singer, S, Singh, B, Tien, NV, Broudy, T, Mirsaidi, C, Nair, P, Drwiega, P, Miller, J, and Smith, J et al.. "A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples." Cell 173.2 (April 2018): 386-399.e12.
Source
crossref
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
386
End Page
399.e12
DOI
10.1016/j.cell.2018.03.027

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Authors
Sanchez-Vega, F; Mina, M; Armenia, J; Chatila, WK; Luna, A; La, KC; Dimitriadoy, S; Liu, DL; Kantheti, HS; Saghafinia, S; Chakravarty, D; Daian, F; Gao, Q; Bailey, MH; Liang, W-W; Foltz, SM; Shmulevich, I; Ding, L; Heins, Z; Ochoa, A; Gross, B; Gao, J; Zhang, H; Kundra, R; Kandoth, C; Bahceci, I; Dervishi, L; Dogrusoz, U; Zhou, W; Shen, H; Laird, PW; Way, GP; Greene, CS; Liang, H; Xiao, Y; Wang, C; Iavarone, A; Berger, AH; Bivona, TG; Lazar, AJ; Hammer, GD; Giordano, T; Kwong, LN; McArthur, G; Huang, C; Tward, AD; Frederick, MJ; McCormick, F; Meyerson, M; Cancer Genome Atlas Research Network, ; Van Allen, EM; Cherniack, AD; Ciriello, G; Sander, C; Schultz, N
MLA Citation
Sanchez-Vega, F, Mina, M, Armenia, J, Chatila, WK, Luna, A, La, KC, Dimitriadoy, S, Liu, DL, Kantheti, HS, Saghafinia, S, Chakravarty, D, Daian, F, Gao, Q, Bailey, MH, Liang, W-W, Foltz, SM, Shmulevich, I, Ding, L, Heins, Z, Ochoa, A, Gross, B, Gao, J, Zhang, H, Kundra, R, Kandoth, C, Bahceci, I, Dervishi, L, Dogrusoz, U, Zhou, W, Shen, H, Laird, PW, Way, GP, Greene, CS, Liang, H, Xiao, Y, Wang, C, Iavarone, A, Berger, AH, Bivona, TG, Lazar, AJ, Hammer, GD, Giordano, T, Kwong, LN, McArthur, G, Huang, C, Tward, AD, Frederick, MJ, McCormick, F, Meyerson, M, Cancer Genome Atlas Research Network, , Van Allen, EM, Cherniack, AD, Ciriello, G, Sander, C, and Schultz, N. "Oncogenic Signaling Pathways in The Cancer Genome Atlas." Cell 173.2 (April 2018): 321-337.e10.
PMID
29625050
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
321
End Page
337.e10
DOI
10.1016/j.cell.2018.03.035

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.

Authors
Malta, TM; Sokolov, A; Gentles, AJ; Burzykowski, T; Poisson, L; Weinstein, JN; Kamińska, B; Huelsken, J; Omberg, L; Gevaert, O; Colaprico, A; Czerwińska, P; Mazurek, S; Mishra, L; Heyn, H; Krasnitz, A; Godwin, AK; Lazar, AJ; Cancer Genome Atlas Research Network, ; Stuart, JM; Hoadley, KA; Laird, PW; Noushmehr, H; Wiznerowicz, M
MLA Citation
Malta, TM, Sokolov, A, Gentles, AJ, Burzykowski, T, Poisson, L, Weinstein, JN, Kamińska, B, Huelsken, J, Omberg, L, Gevaert, O, Colaprico, A, Czerwińska, P, Mazurek, S, Mishra, L, Heyn, H, Krasnitz, A, Godwin, AK, Lazar, AJ, Cancer Genome Atlas Research Network, , Stuart, JM, Hoadley, KA, Laird, PW, Noushmehr, H, and Wiznerowicz, M. "Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation." Cell 173.2 (April 2018): 338-354.e15.
PMID
29625051
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
338
End Page
354.e15
DOI
10.1016/j.cell.2018.03.034

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

Authors
Liu, J; Lichtenberg, T; Hoadley, KA; Poisson, LM; Lazar, AJ; Cherniack, AD; Kovatich, AJ; Benz, CC; Levine, DA; Lee, AV; Omberg, L; Wolf, DM; Shriver, CD; Thorsson, V; Cancer Genome Atlas Research Network, ; Hu, H
MLA Citation
Liu, J, Lichtenberg, T, Hoadley, KA, Poisson, LM, Lazar, AJ, Cherniack, AD, Kovatich, AJ, Benz, CC, Levine, DA, Lee, AV, Omberg, L, Wolf, DM, Shriver, CD, Thorsson, V, Cancer Genome Atlas Research Network, , and Hu, H. "An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics." Cell 173.2 (April 2018): 400-416.e11.
PMID
29625055
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
400
End Page
416.e11
DOI
10.1016/j.cell.2018.02.052

Comprehensive Characterization of Cancer Driver Genes and Mutations.

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Authors
Bailey, MH; Tokheim, C; Porta-Pardo, E; Sengupta, S; Bertrand, D; Weerasinghe, A; Colaprico, A; Wendl, MC; Kim, J; Reardon, B; Ng, PK-S; Jeong, KJ; Cao, S; Wang, Z; Gao, J; Gao, Q; Wang, F; Liu, EM; Mularoni, L; Rubio-Perez, C; Nagarajan, N; Cortés-Ciriano, I; Zhou, DC; Liang, W-W; Hess, JM; Yellapantula, VD; Tamborero, D; Gonzalez-Perez, A; Suphavilai, C; Ko, JY; Khurana, E; Park, PJ; Van Allen, EM; Liang, H; MC3 Working Group, ; Cancer Genome Atlas Research Network, ; Lawrence, MS; Godzik, A; Lopez-Bigas, N; Stuart, J; Wheeler, D; Getz, G; Chen, K; Lazar, AJ; Mills, GB; Karchin, R; Ding, L
MLA Citation
Bailey, MH, Tokheim, C, Porta-Pardo, E, Sengupta, S, Bertrand, D, Weerasinghe, A, Colaprico, A, Wendl, MC, Kim, J, Reardon, B, Ng, PK-S, Jeong, KJ, Cao, S, Wang, Z, Gao, J, Gao, Q, Wang, F, Liu, EM, Mularoni, L, Rubio-Perez, C, Nagarajan, N, Cortés-Ciriano, I, Zhou, DC, Liang, W-W, Hess, JM, Yellapantula, VD, Tamborero, D, Gonzalez-Perez, A, Suphavilai, C, Ko, JY, Khurana, E, Park, PJ, Van Allen, EM, Liang, H, MC3 Working Group, , Cancer Genome Atlas Research Network, , Lawrence, MS, Godzik, A, Lopez-Bigas, N, Stuart, J, Wheeler, D, Getz, G, Chen, K, Lazar, AJ, Mills, GB, Karchin, R, and Ding, L. "Comprehensive Characterization of Cancer Driver Genes and Mutations." Cell 173.2 (April 2018): 371-385.e18.
PMID
29625053
Source
epmc
Published In
Cell
Volume
173
Issue
2
Publish Date
2018
Start Page
371
End Page
385.e18
DOI
10.1016/j.cell.2018.02.060

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types.

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

Authors
Seiler, M; Peng, S; Agrawal, AA; Palacino, J; Teng, T; Zhu, P; Smith, PG; Cancer Genome Atlas Research Network, ; Buonamici, S; Yu, L
MLA Citation
Seiler, M, Peng, S, Agrawal, AA, Palacino, J, Teng, T, Zhu, P, Smith, PG, Cancer Genome Atlas Research Network, , Buonamici, S, and Yu, L. "Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types." Cell Reports 23.1 (April 2018): 282-296.e4.
PMID
29617667
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
282
End Page
296.e4
DOI
10.1016/j.celrep.2018.01.088

Systematic Analysis of Splice-Site-Creating Mutations in Cancer.

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

Authors
Jayasinghe, RG; Cao, S; Gao, Q; Wendl, MC; Vo, NS; Reynolds, SM; Zhao, Y; Climente-González, H; Chai, S; Wang, F; Varghese, R; Huang, M; Liang, W-W; Wyczalkowski, MA; Sengupta, S; Li, Z; Payne, SH; Fenyö, D; Miner, JH; Walter, MJ; Cancer Genome Atlas Research Network, ; Vincent, B; Eyras, E; Chen, K; Shmulevich, I; Chen, F; Ding, L
MLA Citation
Jayasinghe, RG, Cao, S, Gao, Q, Wendl, MC, Vo, NS, Reynolds, SM, Zhao, Y, Climente-González, H, Chai, S, Wang, F, Varghese, R, Huang, M, Liang, W-W, Wyczalkowski, MA, Sengupta, S, Li, Z, Payne, SH, Fenyö, D, Miner, JH, Walter, MJ, Cancer Genome Atlas Research Network, , Vincent, B, Eyras, E, Chen, K, Shmulevich, I, Chen, F, and Ding, L. "Systematic Analysis of Splice-Site-Creating Mutations in Cancer." Cell Reports 23.1 (April 2018): 270-281.e3.
PMID
29617666
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
270
End Page
281.e3
DOI
10.1016/j.celrep.2018.03.052

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

Authors
Knijnenburg, TA; Wang, L; Zimmermann, MT; Chambwe, N; Gao, GF; Cherniack, AD; Fan, H; Shen, H; Way, GP; Greene, CS; Liu, Y; Akbani, R; Feng, B; Donehower, LA; Miller, C; Shen, Y; Karimi, M; Chen, H; Kim, P; Jia, P; Shinbrot, E; Zhang, S; Liu, J; Hu, H; Bailey, MH; Yau, C; Wolf, D; Zhao, Z; Weinstein, JN; Li, L; Ding, L; Mills, GB; Laird, PW; Wheeler, DA; Shmulevich, I; Cancer Genome Atlas Research Network, ; Monnat, RJ; Xiao, Y; Wang, C
MLA Citation
Knijnenburg, TA, Wang, L, Zimmermann, MT, Chambwe, N, Gao, GF, Cherniack, AD, Fan, H, Shen, H, Way, GP, Greene, CS, Liu, Y, Akbani, R, Feng, B, Donehower, LA, Miller, C, Shen, Y, Karimi, M, Chen, H, Kim, P, Jia, P, Shinbrot, E, Zhang, S, Liu, J, Hu, H, Bailey, MH, Yau, C, Wolf, D, Zhao, Z, Weinstein, JN, Li, L, Ding, L, Mills, GB, Laird, PW, Wheeler, DA, Shmulevich, I, Cancer Genome Atlas Research Network, , Monnat, RJ, Xiao, Y, and Wang, C. "Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas." Cell Reports 23.1 (April 2018): 239-254.e6.
PMID
29617664
Source
epmc
Published In
Cell Reports
Volume
23
Issue
1
Publish Date
2018
Start Page
239
End Page
254.e6
DOI
10.1016/j.celrep.2018.03.076

Sonic Hedgehog Immunohistochemistry Improves Inter-observer Agreement for Ballooning and the Diagnosis of Nonalcoholic Steatohepatitis (NASH) among Less Experienced Liver Pathologists

Authors
Schild, M; Xu, L; Suzuki, A; Cardona, D; Clinton, L; McCall, S; Pendse, A; Zhang, X; Abdelmalek, MF; Diehl, AM; Guy, C
MLA Citation
Schild, M, Xu, L, Suzuki, A, Cardona, D, Clinton, L, McCall, S, Pendse, A, Zhang, X, Abdelmalek, MF, Diehl, AM, and Guy, C. "Sonic Hedgehog Immunohistochemistry Improves Inter-observer Agreement for Ballooning and the Diagnosis of Nonalcoholic Steatohepatitis (NASH) among Less Experienced Liver Pathologists." 107th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP). March 17, 2018 - March 23, 2018. Vancouver, CANADA.: NATURE PUBLISHING GROUP, March 1, 2018.
Source
wos
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
31
Publish Date
2018
Start Page
648
End Page
649

Sonic Hedgehog Immunohistochemistry Improves Inter-observer Agreement for Ballooning and the Diagnosis of Nonalcoholic Steatohepatitis (NASH) among Less Experienced Liver Pathologists

Authors
Schild, M; Xu, L; Suzuki, A; Cardona, D; Clinton, L; McCall, S; Pendse, A; Zhang, X; Abdelmalek, MF; Diehl, AM; Guy, C
MLA Citation
Schild, M, Xu, L, Suzuki, A, Cardona, D, Clinton, L, McCall, S, Pendse, A, Zhang, X, Abdelmalek, MF, Diehl, AM, and Guy, C. "Sonic Hedgehog Immunohistochemistry Improves Inter-observer Agreement for Ballooning and the Diagnosis of Nonalcoholic Steatohepatitis (NASH) among Less Experienced Liver Pathologists." 107th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP). March 17, 2018 - March 23, 2018. Vancouver, CANADA.: NATURE PUBLISHING GROUP, March 1, 2018.
Source
wos
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
31
Publish Date
2018
Start Page
648
End Page
649

MFAP5 Distinguishes Between Benign Desmoplasia-Like Reaction and True Desmoplasia in Invasive Adenocarcinoma of the Gallbladder.

Authors
Xu, L; Zhao, L; Hemmerich, A; Ferguson, L; Guy, C; McCall, S; Cardona, D; Hart, J; Zhang, X
MLA Citation
Xu, L, Zhao, L, Hemmerich, A, Ferguson, L, Guy, C, McCall, S, Cardona, D, Hart, J, and Zhang, X. "MFAP5 Distinguishes Between Benign Desmoplasia-Like Reaction and True Desmoplasia in Invasive Adenocarcinoma of the Gallbladder." 107th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP). March 17, 2018 - March 23, 2018. Vancouver, CANADA.: NATURE PUBLISHING GROUP, March 1, 2018.
Source
wos
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
31
Publish Date
2018
Start Page
692
End Page
693

MFAP5 Distinguishes Between Benign Desmoplasia-Like Reaction and True Desmoplasia in Invasive Adenocarcinoma of the Gallbladder.

Authors
Xu, L; Zhao, L; Hemmerich, A; Ferguson, L; Guy, C; McCall, S; Cardona, D; Hart, J; Zhang, X
MLA Citation
Xu, L, Zhao, L, Hemmerich, A, Ferguson, L, Guy, C, McCall, S, Cardona, D, Hart, J, and Zhang, X. "MFAP5 Distinguishes Between Benign Desmoplasia-Like Reaction and True Desmoplasia in Invasive Adenocarcinoma of the Gallbladder." 107th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP). March 17, 2018 - March 23, 2018. Vancouver, CANADA.: NATURE PUBLISHING GROUP, March 1, 2018.
Source
wos
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
31
Publish Date
2018
Start Page
692
End Page
693

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.

Authors
Schaub, FX; Dhankani, V; Berger, AC; Trivedi, M; Richardson, AB; Shaw, R; Zhao, W; Zhang, X; Ventura, A; Liu, Y; Ayer, DE; Hurlin, PJ; Cherniack, AD; Eisenman, RN; Bernard, B; Grandori, C; Cancer Genome Atlas Network,
MLA Citation
Schaub, FX, Dhankani, V, Berger, AC, Trivedi, M, Richardson, AB, Shaw, R, Zhao, W, Zhang, X, Ventura, A, Liu, Y, Ayer, DE, Hurlin, PJ, Cherniack, AD, Eisenman, RN, Bernard, B, Grandori, C, and Cancer Genome Atlas Network, . "Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas." Cell Systems 6.3 (March 2018): 282-300.e2.
PMID
29596783
Source
epmc
Published In
Cell Systems
Volume
6
Issue
3
Publish Date
2018
Start Page
282
End Page
300.e2
DOI
10.1016/j.cels.2018.03.003

Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.

The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.

Authors
Ellrott, K; Bailey, MH; Saksena, G; Covington, KR; Kandoth, C; Stewart, C; Hess, J; Ma, S; Chiotti, KE; McLellan, M; Sofia, HJ; Hutter, C; Getz, G; Wheeler, D; Ding, L; MC3 Working Group, ; Cancer Genome Atlas Research Network,
MLA Citation
Ellrott, K, Bailey, MH, Saksena, G, Covington, KR, Kandoth, C, Stewart, C, Hess, J, Ma, S, Chiotti, KE, McLellan, M, Sofia, HJ, Hutter, C, Getz, G, Wheeler, D, Ding, L, MC3 Working Group, , and Cancer Genome Atlas Research Network, . "Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines." Cell Systems 6.3 (March 2018): 271-281.e7.
PMID
29596782
Source
epmc
Published In
Cell Systems
Volume
6
Issue
3
Publish Date
2018
Start Page
271
End Page
281.e7
DOI
10.1016/j.cels.2018.03.002

Metastatic Renal Cell Carcinoma as Solitary Subcentimeter Polypoid Gastric Mucosal Lesions: Clinicopathologic Analysis of Five Cases.

The stomach is an uncommon site for metastatic carcinoma. Approximately 6% of renal cell carcinomas (RCCs) may metastasize to the stomach. The majority of the reported metastatic RCCs in the stomach presented as large masses or ulcers greater than a centimeter in size. It is very rare to encounter metastatic RCC as a solitary small polypoid gastric mucosal lesion.In this study, we collected surgical pathology cases of gastric metastasis from RCC that measured 1.0 cm or less at the time of endoscopy. The clinicopathological characteristics were analyzed.Five patients with subcentimeter metastatic RCC involving the gastric mucosa were identified. The clinical presentation for upper endoscopic examination was non-specific. Two of the five patients did not have a known history of RCC. In the three patients with a previous history of RCC, the interval from primary RCC diagnosis to the detection of gastric mucosal metastasis was 5, 6, and 10 years, respectively. Endoscopically, all the lesions were solitary, ranging in size from 0.4 to 1 cm. Histologically, all five cases were of the clear cell type consisting of a bland clear cell proliferation within the lamina propria. Although the tumor cells were relatively bland, the presence of clear cytoplasm, nuclear membrane irregularity, occasional enlarged hyperchromatic atypical nuclei, and destructive growth in the center of the lesion should promote immunohistochemical workup. Immunohistochemically, the RCC cells exhibited at least patchy immunoreactivity for cytokeratin and RCC markers. In two cases, there were many CD68 positive foamy histiocytes intermingled with the tumor cells.Metastatic RCC can rarely present as subcentimeter polypoid gastric mucosal lesions. The remote or unknown history of RCC, the non-specific endoscopic appearance, and the bland histological features may lead to a potential diagnostic pitfall. It is of importance to raise the awareness of such an unusual presentation of metastatic RCC in the stomach and to include metastatic RCC in the differential diagnosis for gastric mucosal polyps with clear cell morphology.

Authors
Hemmerich, A; Shaar, M; Burbridge, R; Guy, CD; McCall, SJ; Cardona, DM; Zhang, X; Lai, J; Zhang, X
MLA Citation
Hemmerich, A, Shaar, M, Burbridge, R, Guy, CD, McCall, SJ, Cardona, DM, Zhang, X, Lai, J, and Zhang, X. "Metastatic Renal Cell Carcinoma as Solitary Subcentimeter Polypoid Gastric Mucosal Lesions: Clinicopathologic Analysis of Five Cases." Gastroenterology research 11.1 (February 23, 2018): 25-30.
Website
https://hdl.handle.net/10161/17212
PMID
29511402
Source
epmc
Published In
Gastroenterology Research
Volume
11
Issue
1
Publish Date
2018
Start Page
25
End Page
30
DOI
10.14740/gr952w

The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years.

The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents.

Authors
McCall, SJ; Branton, PA; Blanc, VM; Dry, SM; Gastier-Foster, JM; Harrison, JH; Jewell, SD; Dash, RC; Obeng, RC; Rose, J; Mateski, DL; Liubinskas, A; Robb, JA; Ramirez, NC; Shea, K
MLA Citation
McCall, SJ, Branton, PA, Blanc, VM, Dry, SM, Gastier-Foster, JM, Harrison, JH, Jewell, SD, Dash, RC, Obeng, RC, Rose, J, Mateski, DL, Liubinskas, A, Robb, JA, Ramirez, NC, and Shea, K. "The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years." Biopreservation and Biobanking 16.1 (February 2, 2018): 16-22.
PMID
29394087
Source
epmc
Published In
Biopreservation and Biobanking
Volume
16
Issue
1
Publish Date
2018
Start Page
16
End Page
22
DOI
10.1089/bio.2017.0108

Immune Activation in Early-Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab.

Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non-small cell lung cancer (NSCLC) patients.Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles.Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs.Conclusions: This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. Clin Cancer Res; 23(24); 7474-82. ©2017 AACR.

Authors
Yi, JS; Ready, N; Healy, P; Dumbauld, C; Osborne, R; Berry, M; Shoemaker, D; Clarke, J; Crawford, J; Tong, B; Harpole, D; D'Amico, TA; McSherry, F; Dunphy, F; McCall, SJ; Christensen, JD; Wang, X; Weinhold, KJ
MLA Citation
Yi, JS, Ready, N, Healy, P, Dumbauld, C, Osborne, R, Berry, M, Shoemaker, D, Clarke, J, Crawford, J, Tong, B, Harpole, D, D'Amico, TA, McSherry, F, Dunphy, F, McCall, SJ, Christensen, JD, Wang, X, and Weinhold, KJ. "Immune Activation in Early-Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 23.24 (December 2017): 7474-7482.
PMID
28951518
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
23
Issue
24
Publish Date
2017
Start Page
7474
End Page
7482
DOI
10.1158/1078-0432.ccr-17-2005

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Authors
Singleton, KR; Crawford, L; Tsui, E; Manchester, HE; Maertens, O; Liu, X; Liberti, MV; Magpusao, AN; Stein, EM; Tingley, JP; Frederick, DT; Boland, GM; Flaherty, KT; McCall, SJ; Krepler, C; Sproesser, K; Herlyn, M; Adams, DJ; Locasale, JW; Cichowski, K; Mukherjee, S; Wood, KC
MLA Citation
Singleton, KR, Crawford, L, Tsui, E, Manchester, HE, Maertens, O, Liu, X, Liberti, MV, Magpusao, AN, Stein, EM, Tingley, JP, Frederick, DT, Boland, GM, Flaherty, KT, McCall, SJ, Krepler, C, Sproesser, K, Herlyn, M, Adams, DJ, Locasale, JW, Cichowski, K, Mukherjee, S, and Wood, KC. "Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence." Cell Reports 21.10 (December 2017): 2796-2812.
PMID
29212027
Source
epmc
Published In
Cell Reports
Volume
21
Issue
10
Publish Date
2017
Start Page
2796
End Page
2812
DOI
10.1016/j.celrep.2017.11.022

Overexpression of SOX11 and TFE3 in Solid-Pseudopapillary Neoplasms of the Pancreas.

To characterize the expression of SOX11 and TFE3 proteins in solid-pseudopapillary neoplasms (SPNs) and their histologic mimickers.Immunohistochemistry for SOX11, TFE3, and β-catenin was performed on 31 cases of surgically resected SPNs. Neuroendocrine tumors, acinar cell carcinomas, and pancreatoblastomas served as controls.Nuclear immunoreactivity for SOX11 was detected in all SPNs and five of 31 control tumors. Nuclear immunoreactivity for TFE3 was detected in 30 SPNs and three control tumors. Nuclear immunoreactivity for β-catenin was detected in all SPNs and four control tumors. The combination of three markers as immunohistochemical panels resulted in optimal sensitivity and specificity.Both SOX11 and TFE3 were overexpressed in SPNs and may be involved in the pathogenesis. Clinically, SOX11 and TFE3 can be potentially used as diagnostic markers in distinguishing indeterminate SPNs from their histologic mimickers.

Authors
Harrison, G; Hemmerich, A; Guy, C; Perkinson, K; Fleming, D; McCall, S; Cardona, D; Zhang, X
MLA Citation
Harrison, G, Hemmerich, A, Guy, C, Perkinson, K, Fleming, D, McCall, S, Cardona, D, and Zhang, X. "Overexpression of SOX11 and TFE3 in Solid-Pseudopapillary Neoplasms of the Pancreas." American Journal of Clinical Pathology 149.1 (December 2017): 67-75.
PMID
29272888
Source
epmc
Published In
American Journal of Clinical Pathology
Volume
149
Issue
1
Publish Date
2017
Start Page
67
End Page
75
DOI
10.1093/ajcp/aqx142

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation.

Although cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was to assess ESMG proliferation and differentiation in a 3-dimensional culture model.We evaluated proliferation in human ESMGs from normal and diseased tissue by proliferating cell nuclear antigen immunohistochemistry. Next, we compared 5-ethynyl-2'-deoxyuridine labeling in porcine ESMGs in vivo before and after esophageal injury with a novel in vitro porcine organoid ESMG model. Microarray analysis of ESMGs in culture was compared with squamous epithelium and fresh ESMGs.Marked proliferation was observed in human ESMGs of diseased tissue. This activated ESMG state was recapitulated after esophageal injury in an in vivo porcine model, ESMGs assumed a ductal appearance with increased proliferation compared with control. Isolated and cultured porcine ESMGs produced buds with actively cycling cells and passaged to form epidermal growth factor-dependent spheroids. These spheroids were highly proliferative and were passaged multiple times. Two phenotypes of spheroids were identified: solid squamous (P63+) and hollow/ductal (cytokeratin 7+). Microarray analysis showed spheroids to be distinct from parent ESMGs and enriched for columnar transcripts.Our results suggest that the activated ESMG state, seen in both human disease and our porcine model, may provide a source of cells to repopulate damaged epithelium in a normal manner (squamous) or abnormally (columnar epithelium). This culture model will allow the evaluation of factors that drive ESMGs in the regeneration of injured epithelium. The raw microarray data have been uploaded to the National Center for Biotechnology Information Gene Expression Omnibus (accession number: GSE100543).

Authors
von Furstenberg, RJ; Li, J; Stolarchuk, C; Feder, R; Campbell, A; Kruger, L; Gonzalez, LM; Blikslager, AT; Cardona, DM; McCall, SJ; Henning, SJ; Garman, KS
MLA Citation
von Furstenberg, RJ, Li, J, Stolarchuk, C, Feder, R, Campbell, A, Kruger, L, Gonzalez, LM, Blikslager, AT, Cardona, DM, McCall, SJ, Henning, SJ, and Garman, KS. "Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation." Cellular and Molecular Gastroenterology and Hepatology 4.3 (November 2017): 385-404.
PMID
28936470
Source
epmc
Published In
Cellular and Molecular Gastroenterology and Hepatology
Volume
4
Issue
3
Publish Date
2017
Start Page
385
End Page
404
DOI
10.1016/j.jcmgh.2017.07.005

Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair.

Esophageal injury is a risk factor for diseases such as Barrett's esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pathogenesis of BE and is present in ESMGs. To test our hypothesis that ESMGs activate after esophageal injury with an increase in proliferation, generation of a ductal phenotype, and expression of SOX9, we developed a porcine model of esophageal injury and repair using radiofrequency ablation (RFA). The porcine esophagus contains ESMGs, and RFA produces a consistent and reproducible mucosal injury in the esophagus. Here we present a temporal assessment of this model of esophageal repair. Porcine esophagus was evaluated at 0, 6, 18, 24, 48, and 72 h and 5 and 7 days following RFA and compared with control uninjured esophagus. Following RFA, ESMGs demonstrated an increase in ductal phenotype, echoing our prior studies in humans. Proliferation increased in both squamous epithelium and ESMGs postinjury with a prominent population of SOX9-positive cells in ESMGs postinjury. This model promises to be useful in future experiments evaluating mechanisms of esophageal repair.NEW & NOTEWORTHY A novel porcine model of injury and repair using radiofrequency ablation has been developed, allowing for reproducible injury to the esophagus to study repair in an animal model with esophageal submucosal glands, a key anatomical feature and missing in rodent models but possibly harboring progenitor cells. There is a strong translational component to this porcine model given the anatomical and physiological similarities between pigs and humans.

Authors
Krüger, L; Gonzalez, LM; Pridgen, TA; McCall, SJ; von Furstenberg, RJ; Harnden, I; Carnighan, GE; Cox, AM; Blikslager, AT; Garman, KS
MLA Citation
Krüger, L, Gonzalez, LM, Pridgen, TA, McCall, SJ, von Furstenberg, RJ, Harnden, I, Carnighan, GE, Cox, AM, Blikslager, AT, and Garman, KS. "Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair." American Journal of Physiology. Gastrointestinal and Liver Physiology 313.3 (September 2017): G180-G191.
PMID
28572084
Source
epmc
Published In
American Journal of Physiology Gastrointestinal and Liver Physiology
Volume
313
Issue
3
Publish Date
2017
Start Page
G180
End Page
G191
DOI
10.1152/ajpgi.00036.2017

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

Authors
Anderson, GR; Winter, PS; Lin, KH; Nussbaum, DP; Cakir, M; Stein, EM; Soderquist, RS; Crawford, L; Leeds, JC; Newcomb, R; Stepp, P; Yip, C; Wardell, SE; Tingley, JP; Ali, M; Xu, M; Ryan, M; McCall, SJ; McRee, AJ; Counter, CM; Der, CJ; Wood, KC
MLA Citation
Anderson, GR, Winter, PS, Lin, KH, Nussbaum, DP, Cakir, M, Stein, EM, Soderquist, RS, Crawford, L, Leeds, JC, Newcomb, R, Stepp, P, Yip, C, Wardell, SE, Tingley, JP, Ali, M, Xu, M, Ryan, M, McCall, SJ, McRee, AJ, Counter, CM, Der, CJ, and Wood, KC. "A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution." Cell Reports 20.4 (July 2017): 999-1015.
PMID
28746882
Source
epmc
Published In
Cell Reports
Volume
20
Issue
4
Publish Date
2017
Start Page
999
End Page
1015
DOI
10.1016/j.celrep.2017.07.006

BEST IN PHYSICS (IMAGING): X-Ray Diffraction Spectral Imaging for Breast Cancer Assessment

Authors
Spencer, J; Carter, J; Buxton, C; Leung, C; McCall, S; Greenberg, J; Kapadia, A
MLA Citation
Spencer, J, Carter, J, Buxton, C, Leung, C, McCall, S, Greenberg, J, and Kapadia, A. "BEST IN PHYSICS (IMAGING): X-Ray Diffraction Spectral Imaging for Breast Cancer Assessment." June 2017.
Source
wos-lite
Published In
Medical Physics
Volume
44
Issue
6
Publish Date
2017
Start Page
3292
End Page
3292

Professional Practice Evaluation for Pathologists: The Development, Life, and Death of the Evalumetrics Program.

- In 2008, the Joint Commission (JC) implemented a standard mandating formal monitoring of physician professional performance as part of the process of granting and maintaining practice privileges.- To create a pathology-specific management tool to aid pathologists in constructing a professional practice-monitoring program, thereby meeting the JC mandate.- A total of 105 College of American Pathologists (CAP)-defined metrics were created. Metrics were based on the job descriptions of pathologists' duties in the laboratory, and metric development was aided by experience from the Q-Probes and Q-Tracks programs. The program was offered in a Web-based format, allowing secure data entry, customization of metrics, and central data collection for future benchmarking.- The program was live for 3 years, with 347 pathologists subscribed from 61 practices (median, 4 per institution; range, 1-35). Subscribers used 93 of the CAP-defined metrics and created 109 custom metrics. The median number of CAP-defined metrics used per pathologist was 5 (range, 1-43), and the median custom-defined metrics per pathologist was 2 (range, 1-5). Most frequently, 1 to 3 metrics were monitored (42.7%), with 20% each following 4 to 6 metrics, 5 to 9 metrics, or greater than 10 metrics. Anatomic pathology metrics were used more commonly than clinical pathology metrics. Owing to low registration, the program was discontinued in 2016.- Through careful vetting of metrics it was possible to develop a pathologist-specific management tool to address the JC mandate. While this initial product failed, valuable metrics were developed and implementation knowledge was gained that may be used to address new regulatory requirements for emerging value-based payment systems.

Authors
Volmar, KE; McCall, SJ; Schifman, RB; Talbert, ML; Tworek, JA; Hulkower, KI; Guidi, AJ; Nakhleh, RE; Souers, RJ; Bashleben, CP; Blond, BJ
MLA Citation
Volmar, KE, McCall, SJ, Schifman, RB, Talbert, ML, Tworek, JA, Hulkower, KI, Guidi, AJ, Nakhleh, RE, Souers, RJ, Bashleben, CP, and Blond, BJ. "Professional Practice Evaluation for Pathologists: The Development, Life, and Death of the Evalumetrics Program." Archives of pathology & laboratory medicine 141.4 (April 2017): 551-558.
PMID
28353384
Source
epmc
Published In
Archives of Pathology & Laboratory Medicine
Volume
141
Issue
4
Publish Date
2017
Start Page
551
End Page
558
DOI
10.5858/arpa.2016-0275-cp

Serum Amyloid A (SAA) and C-Reactive Protein (CRP) Are Commonly Positive in Hepatocellular Carcinoma and Expression Levels Stratify According to Etiology and the Absence of Cirrhosis

Authors
Shaar, M; Suzuki, A; Poster, C; de Ridder, G; Zhang, X; Cronin, MK; McCall, S; Cardona, D; Abdelmalek, M; Pizzo, S; Jiang, XS; Lefaivre, M; Guy, C
MLA Citation
Shaar, M, Suzuki, A, Poster, C, de Ridder, G, Zhang, X, Cronin, MK, McCall, S, Cardona, D, Abdelmalek, M, Pizzo, S, Jiang, XS, Lefaivre, M, and Guy, C. "Serum Amyloid A (SAA) and C-Reactive Protein (CRP) Are Commonly Positive in Hepatocellular Carcinoma and Expression Levels Stratify According to Etiology and the Absence of Cirrhosis." February 2017.
Source
wos-lite
Published In
Laboratory Investigation
Volume
97
Publish Date
2017
Start Page
424A
End Page
425A

Metastatic Renal Cell Carcinoma Presenting as a Solitary Subcentimeter Gastroesophageal Mucosal Polyp: Report of 5 Cases

Authors
Sham, M; Guy, C; McCall, S; Cardona, D; Zhang, X
MLA Citation
Sham, M, Guy, C, McCall, S, Cardona, D, and Zhang, X. "Metastatic Renal Cell Carcinoma Presenting as a Solitary Subcentimeter Gastroesophageal Mucosal Polyp: Report of 5 Cases." February 2017.
Source
wos-lite
Published In
Laboratory Investigation
Volume
97
Publish Date
2017
Start Page
258A
End Page
258A

TFE3 and SOX11 as Novel Diagnostic Markers for Solid Pseudopapillary Neoplasms

Authors
Harrison, G; Hemmerich, A; Cardona, D; Guy, C; McCall, S; Zhang, X
MLA Citation
Harrison, G, Hemmerich, A, Cardona, D, Guy, C, McCall, S, and Zhang, X. "TFE3 and SOX11 as Novel Diagnostic Markers for Solid Pseudopapillary Neoplasms." February 2017.
Source
wos-lite
Published In
Laboratory Investigation
Volume
97
Publish Date
2017
Start Page
174A
End Page
174A

TFE3 and SOX11 as Novel Diagnostic Markers for Solid Pseudopapillary Neoplasms

Authors
Harrison, G; Hemmerich, A; Cardona, D; Guy, C; McCall, S; Zhang, X
MLA Citation
Harrison, G, Hemmerich, A, Cardona, D, Guy, C, McCall, S, and Zhang, X. "TFE3 and SOX11 as Novel Diagnostic Markers for Solid Pseudopapillary Neoplasms." February 2017.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
30
Publish Date
2017
Start Page
174A
End Page
174A

Serum Amyloid A (SAA) and C-Reactive Protein (CRP) Are Commonly Positive in Hepatocellular Carcinoma and Expression Levels Stratify According to Etiology and the Absence of Cirrhosis

Authors
Shaar, M; Suzuki, A; Poster, C; de Ridder, G; Zhang, X; Cronin, MK; McCall, S; Cardona, D; Abdelmalek, M; Pizzo, S; Jiang, XS; Lefaivre, M; Guy, C
MLA Citation
Shaar, M, Suzuki, A, Poster, C, de Ridder, G, Zhang, X, Cronin, MK, McCall, S, Cardona, D, Abdelmalek, M, Pizzo, S, Jiang, XS, Lefaivre, M, and Guy, C. "Serum Amyloid A (SAA) and C-Reactive Protein (CRP) Are Commonly Positive in Hepatocellular Carcinoma and Expression Levels Stratify According to Etiology and the Absence of Cirrhosis." February 2017.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
30
Publish Date
2017
Start Page
424A
End Page
425A

Metastatic Renal Cell Carcinoma Presenting as a Solitary Subcentimeter Gastroesophageal Mucosal Polyp: Report of 5 Cases

Authors
Shaar, M; Guy, C; McCall, S; Cardona, D; Zhang, X
MLA Citation
Shaar, M, Guy, C, McCall, S, Cardona, D, and Zhang, X. "Metastatic Renal Cell Carcinoma Presenting as a Solitary Subcentimeter Gastroesophageal Mucosal Polyp: Report of 5 Cases." February 2017.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
30
Publish Date
2017
Start Page
258A
End Page
258A

Integrated genomic characterization of oesophageal carcinoma.

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.

Authors
Cancer Genome Atlas Research Network, ; Analysis Working Group: Asan University, ; BC Cancer Agency, ; Brigham and Women’s Hospital, ; Broad Institute, ; Brown University, ; Case Western Reserve University, ; Dana-Farber Cancer Institute, ; Duke University, ; Greater Poland Cancer Centre, ; Harvard Medical School, ; Institute for Systems Biology, ; KU Leuven, ; Mayo Clinic, ; Memorial Sloan Kettering Cancer Center, ; National Cancer Institute, ; Nationwide Children’s Hospital, ; Stanford University, ; University of Alabama, ; University of Michigan, ; University of North Carolina, ; University of Pittsburgh, ; University of Rochester, ; University of Southern California, ; University of Texas MD Anderson Cancer Center, ; University of Washington, ; Van Andel Research Institute, ; Vanderbilt University, ; Washington University, ; Genome Sequencing Center: Broad Institute, ; Washington University in St. Louis, ; Genome Characterization Centers: BC Cancer Agency, ; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, ; University of Southern California Epigenome Center, ; Genome Data Analysis Centers: Broad Institute, ; Brown University:, ; University of California Santa Cruz, ; Biospecimen Core Resource: International Genomics Consortium, ; Research Institute at Nationwide Children’s Hospital, ; Tissue Source Sites: Analytic Biologic Services, ; Asan Medical Center, ; Asterand Bioscience, ; Barretos Cancer Hospital, ; BioreclamationIVT, ; Botkin Municipal Clinic, ; Chonnam National University Medical School, ; Christiana Care Health System, ; Cureline, ; Emory University, ; Erasmus University, ; Indiana University School of Medicine, ; Institute of Oncology of Moldova, ; International Genomics Consortium, ; Invidumed, ; Israelitisches Krankenhaus Hamburg, ; Keimyung University School of Medicine, ; National Cancer Center Goyang, ; Ontario Tumour Bank, ; Peter MacCallum Cancer Centre, ; Pusan National University Medical School, ; Ribeirão Preto Medical School, ; St. Joseph’s Hospital &Medical Center, ; St. Petersburg Academic University, ; Tayside Tissue Bank, ; University of Dundee, ; University of Kansas Medical Center, ; University of North Carolina at Chapel Hill, ; University of Pittsburgh School of Medicine, ; Disease Working Group: Duke University, ; Yonsei University College of Medicine, ; Data Coordination Center: CSRA Inc., ; Project Team: National Institutes of Health,
MLA Citation
Cancer Genome Atlas Research Network, , Analysis Working Group: Asan University, , BC Cancer Agency, , Brigham and Women’s Hospital, , Broad Institute, , Brown University, , Case Western Reserve University, , Dana-Farber Cancer Institute, , Duke University, , Greater Poland Cancer Centre, , Harvard Medical School, , Institute for Systems Biology, , KU Leuven, , Mayo Clinic, , Memorial Sloan Kettering Cancer Center, , National Cancer Institute, , Nationwide Children’s Hospital, , Stanford University, , University of Alabama, , University of Michigan, , University of North Carolina, , University of Pittsburgh, , University of Rochester, , University of Southern California, , University of Texas MD Anderson Cancer Center, , University of Washington, , Van Andel Research Institute, , Vanderbilt University, , Washington University, , Genome Sequencing Center: Broad Institute, , Washington University in St. Louis, , Genome Characterization Centers: BC Cancer Agency, , Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, , University of Southern California Epigenome Center, , Genome Data Analysis Centers: Broad Institute, , Brown University:, , University of California Santa Cruz, , Biospecimen Core Resource: International Genomics Consortium, , Research Institute at Nationwide Children’s Hospital, , Tissue Source Sites: Analytic Biologic Services, , Asan Medical Center, , Asterand Bioscience, , Barretos Cancer Hospital, , BioreclamationIVT, , Botkin Municipal Clinic, , Chonnam National University Medical School, , Christiana Care Health System, , Cureline, , Emory University, , Erasmus University, , Indiana University School of Medicine, , Institute of Oncology of Moldova, , International Genomics Consortium, , Invidumed, , Israelitisches Krankenhaus Hamburg, , Keimyung University School of Medicine, , National Cancer Center Goyang, , Ontario Tumour Bank, , Peter MacCallum Cancer Centre, , Pusan National University Medical School, , Ribeirão Preto Medical School, , St. Joseph’s Hospital &Medical Center, , St. Petersburg Academic University, , Tayside Tissue Bank, , University of Dundee, , University of Kansas Medical Center, , University of North Carolina at Chapel Hill, , University of Pittsburgh School of Medicine, , Disease Working Group: Duke University, , Yonsei University College of Medicine, , Data Coordination Center: CSRA Inc., , and Project Team: National Institutes of Health, . "Integrated genomic characterization of oesophageal carcinoma." Nature 541.7636 (January 4, 2017): 169-175.
PMID
28052061
Source
epmc
Published In
Nature
Volume
541
Issue
7636
Publish Date
2017
Start Page
169
End Page
175
DOI
10.1038/nature20805

Coded aperture coherent scatter spectral imaging for assessment of breast cancers: An ex-vivo demonstration

© 2017 SPIE. A Coded Aperture Coherent Scatter Spectral Imaging (CACSSI) system was developed in our group to differentiate cancer and healthy tissue in the breast. The utility of the experimental system was previously demonstrated using anthropomorphic breast phantoms and breast biopsy specimens. Here we demonstrate CACSSI utility in identifying tumor margins in real time using breast lumpectomy specimens. Fresh lumpectomy specimens were obtained from Surgical Pathology with the suspected cancerous area designated on the specimen. The specimens were scanned using CACSSI to obtain spectral scatter signatures at multiple locations within the tumor and surrounding tissue. The spectral reconstructions were matched with literature form-factors to classify the tissue as cancerous or non-cancerous. The findings were then compared against pathology reports to confirm the presence and location of the tumor. The system was found to be capable of consistently differentiating cancerous and healthy regions in the breast with spatial resolution of 5 mm. Tissue classification results from the scanned specimens could be correlated with pathology results. We now aim to develop CACSSI as a clinical imaging tool to aid breast cancer assessment and other diagnostic purposes.

Authors
Spencer, JR; Carter, JE; Leung, CK; McCall, SJ; Greenberg, JA; Kapadia, AJ
MLA Citation
Spencer, JR, Carter, JE, Leung, CK, McCall, SJ, Greenberg, JA, and Kapadia, AJ. "Coded aperture coherent scatter spectral imaging for assessment of breast cancers: An ex-vivo demonstration." January 1, 2017.
Source
scopus
Published In
Progress in Biomedical Optics and Imaging Proceedings of Spie
Volume
10132
Publish Date
2017
DOI
10.1117/12.2253975

Biobanking-Budgets and the Role of Pathology Biobanks in Precision Medicine.

Biobanks have become an important component of the routine practice of pathology. At the 2016 meeting of the Association of Pathology Chairs, a series of presentations covered several important aspects of biobanking. An often overlooked aspect of biobanking is the fiscal considerations. A biobank budget must address the costs of consenting, procuring, processing, and preserving high-quality biospecimens. Multiple revenue streams will frequently be necessary to create a sustainable biobank; partnering with other key stakeholders has been shown to be successful at academic institutions which may serve as a model. Biobanking needs to be a deeply science-driven and innovating process so that specimens help transform patient-centered clinical and basic research (ie, fulfill the promise of precision medicine). Pathology's role must be at the center of the biobanking process. This ensures that optimal research samples are collected while guaranteeing that clinical diagnostics are never impaired. Biobanks will continue to grow as important components in the mission of pathology, especially in the era of precision medicine.

Authors
Andry, C; Duffy, E; Moskaluk, CA; McCall, S; Roehrl, MHA; Remick, D
MLA Citation
Andry, C, Duffy, E, Moskaluk, CA, McCall, S, Roehrl, MHA, and Remick, D. "Biobanking-Budgets and the Role of Pathology Biobanks in Precision Medicine." Academic Pathology 4 (January 2017): 2374289517702924-null.
PMID
28725790
Source
epmc
Published In
Academic Pathology
Volume
4
Publish Date
2017
Start Page
2374289517702924
DOI
10.1177/2374289517702924

Radiographic and endoscopic regression of metastatic gastric cancer to the colon in the setting of 5-aminosalicylic acid use.

Colonic metastases from gastric cancer are a rare phenomenon and sparsely reported in the literature. We report a case of a 59-year-old woman who presented with vague abdominal symptoms and initial computer tomography (CT) imaging suggestive of a colonic apple-core lesion with serial colonoscopic biopsies diagnostic of metastatic signet ring cell gastric adenocarcinoma. This case is unique given the evolving CT and endoscopic findings that suggested a regression in colonic wall thickening in the setting of 5-aminosalicylic acid (5-ASA) use prior to histologic diagnosis.

Authors
Patel, YA; McCall, SJ; Zhang, X; Jaffe, T; Shimpi, RA
MLA Citation
Patel, YA, McCall, SJ, Zhang, X, Jaffe, T, and Shimpi, RA. "Radiographic and endoscopic regression of metastatic gastric cancer to the colon in the setting of 5-aminosalicylic acid use." Journal of gastrointestinal oncology 7.6 (December 2016): E88-E92.
PMID
28078130
Source
epmc
Published In
Journal of Gastrointestinal Oncology
Volume
7
Issue
6
Publish Date
2016
Start Page
E88
End Page
E92
DOI
10.21037/jgo.2016.05.02

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

Authors
Anderson, GR; Wardell, SE; Cakir, M; Crawford, L; Leeds, JC; Nussbaum, DP; Shankar, PS; Soderquist, RS; Stein, EM; Tingley, JP; Winter, PS; Zieser-Misenheimer, EK; Alley, HM; Yllanes, A; Haney, V; Blackwell, KL; McCall, SJ; McDonnell, DP; Wood, KC
MLA Citation
Anderson, GR, Wardell, SE, Cakir, M, Crawford, L, Leeds, JC, Nussbaum, DP, Shankar, PS, Soderquist, RS, Stein, EM, Tingley, JP, Winter, PS, Zieser-Misenheimer, EK, Alley, HM, Yllanes, A, Haney, V, Blackwell, KL, McCall, SJ, McDonnell, DP, and Wood, KC. "PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation." Science Translational Medicine 8.369 (December 2016): 369ra175-null.
Website
http://hdl.handle.net/10161/13335
PMID
27974663
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
369
Publish Date
2016
Start Page
369ra175
DOI
10.1126/scitranslmed.aae0348

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

Authors
Hesler, RA; Huang, JJ; Starr, MD; Treboschi, VM; Bernanke, AG; Nixon, AB; McCall, SJ; White, RR; Blobe, GC
MLA Citation
Hesler, RA, Huang, JJ, Starr, MD, Treboschi, VM, Bernanke, AG, Nixon, AB, McCall, SJ, White, RR, and Blobe, GC. "TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3." Carcinogenesis 37.11 (November 2016): 1041-1051.
PMID
27604902
Source
epmc
Published In
Carcinogenesis
Volume
37
Issue
11
Publish Date
2016
Start Page
1041
End Page
1051
DOI
10.1093/carcin/bgw093

Physician Satisfaction With Clinical Laboratory Services: A College of American Pathologists Q-Probes Study of 81 Institutions.

-Assessment of customer satisfaction is a vital component of the laboratory quality improvement program.-To survey the level of physician satisfaction with hospital clinical laboratory services.-Participating institutions provided demographic information and survey results of physician satisfaction, with specific features of clinical laboratory services individually rated on a scale of 5 (excellent) to 1 (poor).-Eighty-one institutions submitted 2425 surveys. The median overall satisfaction score was 4.2 (10th percentile, 3.6; 90th percentile, 4.6). Of the 16 surveyed areas receiving the highest percentage of excellent/good ratings (combined scores of 4 and 5), quality of results was highest along with test menu adequacy, staff courtesy, and overall satisfaction. Of the 4 categories receiving the lowest percentage values of excellent/good ratings, 3 were related to turnaround time for inpatient "STAT" (tests performed immediately), outpatient STAT, and esoteric tests. The fourth was a new category presented in this survey: ease of electronic order entry. Here, 11.4% (241 of 2121) of physicians assigned below-average (2) or poor (1) scores. The 5 categories deemed most important to physicians included quality of results, turnaround times for inpatient STAT, routine, and outpatient STAT tests, and clinical report format. Overall satisfaction as measured by physician willingness to recommend their laboratory to another physician remains high at 94.5% (2160 of 2286 respondents).-There is a continued trend of high physician satisfaction and loyalty with clinical laboratory services. Physician dissatisfaction with ease of electronic order entry represents a new challenge. Test turnaround times are persistent areas of dissatisfaction, representing areas for improvement.

Authors
McCall, SJ; Souers, RJ; Blond, B; Massie, L
MLA Citation
McCall, SJ, Souers, RJ, Blond, B, and Massie, L. "Physician Satisfaction With Clinical Laboratory Services: A College of American Pathologists Q-Probes Study of 81 Institutions." Archives of Pathology & Laboratory Medicine 140.10 (October 2016): 1098-1103.
PMID
27684982
Source
epmc
Published In
Archives of Pathology & Laboratory Medicine
Volume
140
Issue
10
Publish Date
2016
Start Page
1098
End Page
1103
DOI
10.5858/arpa.2015-0486-cp

Identification and Therapeutic Inhibition of Pathways Driving Resistance to Targeted Breast Cancer Therapies

Authors
Wood, KC; Anderson, GR; Wardell, SE; Jasper, JS; Stein, EM; Martz, CA; Alley, HM; Haney, V; Yllanes, A; Blackwell, KL; McCall, SJ; McDonnell, DP
MLA Citation
Wood, KC, Anderson, GR, Wardell, SE, Jasper, JS, Stein, EM, Martz, CA, Alley, HM, Haney, V, Yllanes, A, Blackwell, KL, McCall, SJ, and McDonnell, DP. "Identification and Therapeutic Inhibition of Pathways Driving Resistance to Targeted Breast Cancer Therapies." JOURNAL OF WOMENS HEALTH 25.9 (September 2016): 976-976.
Source
wos-lite
Published In
Journal of Women'S Health (2002)
Volume
25
Issue
9
Publish Date
2016
Start Page
976
End Page
976

TH-AB-209-10: Breast Cancer Identification Through X-Ray Coherent Scatter Spectral Imaging.

We have previously described the development and testing of a coherent-scatter spectral imaging system for identification of cancer. Our prior evaluations were performed using either tissue surrogate phantoms or formalin-fixed tissue obtained from pathology. Here we present the first results from a scatter imaging study using fresh breast tumor tissues obtained through surgical excision.A coherent-scatter imaging system was built using a clinical X-ray tube, photon counting detectors, and custom-designed coded-apertures. System performance was characterized using calibration phantoms of biological materials. Fresh breast tumors were obtained from patients undergoing mastectomy and lumpectomy surgeries for breast cancer. Each specimen was vacuum-sealed, scanned using the scatter imaging system, and then sent to pathology for histological workup. Scatter images were generated separately for each tissue specimen and analyzed to identify voxels containing malignant tissue. The images were compared against histological analysis (H&E + pathologist identification of tumors) to assess the match between scatter-based and histological diagnosis.In all specimens scanned, the scatter images showed the location of cancerous regions within the specimen. The detection and classification was performed through automated spectral matching without the need for manual intervention. The scatter spectra corresponding to cancer tissue were found to be in agreement with those reported in literature. Inter-patient variability was found to be within limits reported in literature. The scatter images showed agreement with pathologist-identified regions of cancer. Spatial resolution for this configuration of the scanner was determined to be 2-3 mm, and the total scan time for each specimen was under 15 minutes.This work demonstrates the utility of coherent scatter imaging in identifying cancer based on the scatter properties of the tissue. It presents the first results from coherent scatter imaging of fresh (unfixed) breast tissue using our coded-aperture scatter imaging approach for cancer identification.

Authors
Kapadia, A; Morris, R; Albanese, K; Spencer, J; McCall, S; Greenberg, J
MLA Citation
Kapadia, A, Morris, R, Albanese, K, Spencer, J, McCall, S, and Greenberg, J. "TH-AB-209-10: Breast Cancer Identification Through X-Ray Coherent Scatter Spectral Imaging." Medical physics 43.6 (June 2016): 3865-.
PMID
28047602
Source
epmc
Published In
Medical Physics
Volume
43
Issue
6
Publish Date
2016
Start Page
3865
DOI
10.1118/1.4958101

Mixed Adenoneuroendocrine Carcinoma, Amphicrine Type, of the Small Bowel.

Amphicrine-type mixed adenoneuroendocrine carcinomas are exceedingly rare lesions of the gastrointestinal tract, comprising tumor cells simultaneously demonstrating both neuroendocrine and exocrine features. To date, only 14 cases of amphicrine carcinoma have been reported; here we report the first definitive case of amphicrine carcinoma in the small bowel.A 72-year-old woman who sought treatment for nonspecific abdominal complaints was found to have a duodenojejunal junction tumor and underwent radical surgical resection.Morphologically, the tumor consisted of areas of moderately differentiated adenocarcinoma intermingled with areas characteristic of neuroendocrine tumor. The entire tumor showed strong, diffuse immunoreactivity for synaptophysin. Coexpression of exocrine and neuroendocrine features by neoplastic cells indicates bivalent differentiation, and therefore the tumor was classified as an amphicrine carcinoma of the small bowel.Demonstration of amphicrine carcinoma in the small bowel carries implications with regard to the common origin of exocrine and neuroendocrine cells in the gastrointestinal tract.

Authors
Ludmir, EB; McCall, SJ; Cardona, DM; Perkinson, KR; Guy, CD; Zhang, X
MLA Citation
Ludmir, EB, McCall, SJ, Cardona, DM, Perkinson, KR, Guy, CD, and Zhang, X. "Mixed Adenoneuroendocrine Carcinoma, Amphicrine Type, of the Small Bowel." American Journal of Clinical Pathology 145.5 (May 2016): 703-709.
PMID
27124941
Source
epmc
Published In
American Journal of Clinical Pathology
Volume
145
Issue
5
Publish Date
2016
Start Page
703
End Page
709
DOI
10.1093/ajcp/aqw028

Primary high-grade neuroendocrine carcinoma emerging from an adenomatous polyp in the setting of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a rare inherited syndrome that is characterised by innumerable adenomas of the colon and rectum, a high risk of colorectal cancer and a variety of extracolonic manifestations. FAP presents as hundreds to thousands of colonic adenomas beginning in adolescence. The syndrome is associated with less than 1% of all colorectal cancer cases, but there is a nearly 100% lifetime risk of colorectal cancer in individuals with FAP. This case demonstrates a 60-year-old man with FAP who developed high-grade neuroendocrine carcinoma with glandular and squamous differentiation, and regional lymph node and liver metastases. Early diagnosis of FAP is of the utmost importance to start screening colonoscopies to assess disease burden, perform polypectomies and to make management decisions. Neuroendocrine carcinomas rarely occur in patients with FAP, and awareness of this association among general medical physicians and pathologists is essential for the diagnosis and care of these patients.

Authors
Detweiler, CJ; Cardona, DM; Hsu, DS; McCall, SJ
MLA Citation
Detweiler, CJ, Cardona, DM, Hsu, DS, and McCall, SJ. "Primary high-grade neuroendocrine carcinoma emerging from an adenomatous polyp in the setting of familial adenomatous polyposis." BMJ case reports 2016 (February 16, 2016).
PMID
26884076
Source
epmc
Published In
Bmj Case Reports
Volume
2016
Publish Date
2016
DOI
10.1136/bcr-2015-214206

Transcription Factor E3 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm

Authors
Harrison, G; Hemmerich, A; Guy, C; McCall, SJ; Cardona, DM; Zhang, X
MLA Citation
Harrison, G, Hemmerich, A, Guy, C, McCall, SJ, Cardona, DM, and Zhang, X. "Transcription Factor E3 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm." February 2016.
Source
wos-lite
Published In
Laboratory Investigation
Volume
96
Publish Date
2016
Start Page
174A
End Page
174A

Transcription Factor E3 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm

Authors
Harrison, G; Hemmerich, A; Guy, C; McCall, SJ; Cardona, DM; Zhang, X
MLA Citation
Harrison, G, Hemmerich, A, Guy, C, McCall, SJ, Cardona, DM, and Zhang, X. "Transcription Factor E3 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm." February 2016.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
29
Publish Date
2016
Start Page
174A
End Page
174A

Validation of coded aperture coherent scatter spectral imaging for normal and neoplastic breast tissues via surgical pathology

© 2016 SPIE. This study intends to validate the sensitivity and specificity of coded aperture coherent scatter spectral imaging (CACSSI) by comparison to standard histological preparation and pathologic analysis methods used to differentiate normal and neoplastic breast tissues. A composite overlay of the CACSSI rendered image and pathologist interpreted stained sections validate the ability of CACSSI to differentiate normal and neoplastic breast structures ex-vivo. Via comparison to pathologist annotated slides, the CACSSI system may be further optimized to maximize sensitivity and specificity for differentiation of breast carcinomas.

Authors
Morris, RE; Albanese, KE; Lakshmanan, MN; McCall, SJ; Greenberg, JA; Kapadia, AJ
MLA Citation
Morris, RE, Albanese, KE, Lakshmanan, MN, McCall, SJ, Greenberg, JA, and Kapadia, AJ. "Validation of coded aperture coherent scatter spectral imaging for normal and neoplastic breast tissues via surgical pathology." January 1, 2016.
Source
scopus
Published In
Progress in Biomedical Optics and Imaging Proceedings of Spie
Volume
9783
Publish Date
2016
DOI
10.1117/12.2216974

Delayed specimen collection may artifactually damage the mucosal surface in endoscopic mucosal resection specimens from Barrett's esophagus

Authors
Zhang, X; Burbridge, R; Branch, M; Xiao, S; Zhao, L; McCall, SJ; Guy, C; Cardona, D; Garman, K; Waxman, I; Hart, J
MLA Citation
Zhang, X, Burbridge, R, Branch, M, Xiao, S, Zhao, L, McCall, SJ, Guy, C, Cardona, D, Garman, K, Waxman, I, and Hart, J. "Delayed specimen collection may artifactually damage the mucosal surface in endoscopic mucosal resection specimens from Barrett's esophagus." American Journal of Digestive Disease 2.2 (December 30, 2016): 90-94.
Source
manual
Published In
American Journal of Digestive Disease
Volume
2
Issue
2
Publish Date
2015
Start Page
90
End Page
94

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC).We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour.We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

Authors
Garman, KS; Kruger, L; Thomas, S; Swiderska-Syn, M; Moser, BK; Diehl, AM; McCall, SJ
MLA Citation
Garman, KS, Kruger, L, Thomas, S, Swiderska-Syn, M, Moser, BK, Diehl, AM, and McCall, SJ. "Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma." Histopathology 67.6 (December 2015): 771-782.
PMID
25847432
Source
epmc
Published In
Histopathology
Volume
67
Issue
6
Publish Date
2015
Start Page
771
End Page
782
DOI
10.1111/his.12707

The Molecular Taxonomy of Primary Prostate Cancer.

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Authors
Cancer Genome Atlas Research Network,
MLA Citation
Cancer Genome Atlas Research Network, . "The Molecular Taxonomy of Primary Prostate Cancer." Cell 163.4 (November 2015): 1011-1025.
PMID
26544944
Source
epmc
Published In
Cell
Volume
163
Issue
4
Publish Date
2015
Start Page
1011
End Page
1025
DOI
10.1016/j.cell.2015.10.025

Metastatic Gallbladder Cancer Masquerading as Primary Colon Malignancy

Authors
Sun, Z
MLA Citation
Sun, Z. "Metastatic Gallbladder Cancer Masquerading as Primary Colon Malignancy." Clinical Medical Reviews and Case Reports 2.3 (March 31, 2015).
Source
crossref
Published In
Clinical Medical Reviews and Case Reports
Volume
2
Issue
3
Publish Date
2015
DOI
10.23937/2378-3656/1410024

Error Reduction and Prevention in Surgical Pathology

Diagnostic musculoskeletal surgical pathology. Philadelphia: Elsevier; 2004. pp. 1–18. Suriawinata AA, Antonio LB, Thung SN. Liver tissue processing and normal histology. In: Odze RD, Goldblum JR, editors. Surgical pathology of the GI tract, ...

Authors
Nakhleh, RE
MLA Citation
Nakhleh, RE. "Error Reduction and Prevention in Surgical Pathology." Springer, March 3, 2015.
Source
google-books
Publish Date
2015

Mismatch repair gone awry: Management of Lynch syndrome.

The hallmark of Lynch syndrome involves germline mutations of genes important in DNA mismatch repair. Affected family kindreds will have multiple associated malignancies, the most common of which is colorectal adenocarcinoma. Recently, evidence has shown that clinical diagnostic criteria provided by the Amsterdam Criteria and the Bethesda Guidelines must be linked with microsatellite instability testing to correctly diagnose Lynch syndrome. We present a case of metachronous colorectal adenocarcinomas in a patient less than 50 years of age, followed by a discussion of Lynch syndrome, with an emphasis on surveillance and prevention of malignancies.

Authors
Zhang, T; Boswell, EL; McCall, SJ; Hsu, DS
MLA Citation
Zhang, T, Boswell, EL, McCall, SJ, and Hsu, DS. "Mismatch repair gone awry: Management of Lynch syndrome." Critical reviews in oncology/hematology 93.3 (March 2015): 170-179. (Review)
PMID
25459670
Source
epmc
Published In
Critical Reviews in Oncology/Hematology
Volume
93
Issue
3
Publish Date
2015
Start Page
170
End Page
179
DOI
10.1016/j.critrevonc.2014.10.005

Endogenous elevation of plasma cholecystokinin does not prevent gallstones.

Regular gall bladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor-I (PSTI-I, also known as monitor peptide) causes cholecystokinin (CCK) secretion.We proposed that stimulation of CCK release by PSTI would produce gall bladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gall bladder function in a transgenic mouse line (TgN[Psti1]; known hereafter as PSTI-I tg).Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type (WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals.Together with the previously observed decrease in CCK-stimulated gall bladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gall bladder sensitivity to CCK.

Authors
Shahid, RA; Wang, DQ-H; Fee, BE; McCall, SJ; Romac, JM-J; Vigna, SR; Liddle, RA
MLA Citation
Shahid, RA, Wang, DQ-H, Fee, BE, McCall, SJ, Romac, JM-J, Vigna, SR, and Liddle, RA. "Endogenous elevation of plasma cholecystokinin does not prevent gallstones." European journal of clinical investigation 45.3 (March 2015): 237-246.
PMID
25641074
Source
epmc
Published In
European Journal of Clinical Investigation
Volume
45
Issue
3
Publish Date
2015
Start Page
237
End Page
246
DOI
10.1111/eci.12400

Diagnosing Hepatocellular Carcinoma With Immunohistochemistry: Quantitative Assessment of Performance Characteristics for gamma-H2AX, Glypican-3, Clathrin Heavy Chain, and Glutamine Synthetase

Authors
Poster, C; Gustafson, K; Furth, E; McCall, S; Cardona, D; Zhang, X; Lagoo, A; Lefaivre, M; Guy, C
MLA Citation
Poster, C, Gustafson, K, Furth, E, McCall, S, Cardona, D, Zhang, X, Lagoo, A, Lefaivre, M, and Guy, C. "Diagnosing Hepatocellular Carcinoma With Immunohistochemistry: Quantitative Assessment of Performance Characteristics for gamma-H2AX, Glypican-3, Clathrin Heavy Chain, and Glutamine Synthetase." February 2015.
Source
wos-lite
Published In
Laboratory Investigation
Volume
95
Publish Date
2015
Start Page
421A
End Page
421A

Diagnosing Hepatocellular Carcinoma With Immunohistochemistry: Quantitative Assessment of Performance Characteristics for gamma-H2AX, Glypican-3, Clathrin Heavy Chain, and Glutamine Synthetase

Authors
Poster, C; Gustafson, K; Furth, E; McCall, S; Cardona, D; Zhang, X; Lagoo, A; Lefaivre, M; Guy, C
MLA Citation
Poster, C, Gustafson, K, Furth, E, McCall, S, Cardona, D, Zhang, X, Lagoo, A, Lefaivre, M, and Guy, C. "Diagnosing Hepatocellular Carcinoma With Immunohistochemistry: Quantitative Assessment of Performance Characteristics for gamma-H2AX, Glypican-3, Clathrin Heavy Chain, and Glutamine Synthetase." February 2015.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
28
Publish Date
2015
Start Page
421A
End Page
421A

Patterns of failure for stage I ampulla of Vater adenocarcinoma: a single institutional experience.

Ampullary adenocarcinoma is a rare malignancy associated with a relatively favorable prognosis. Given high survival rates in stage I patients reported in small series with surgery alone, adjuvant chemoradiotherapy (CRT) has traditionally been recommended only for patients with high risk disease. Recent population-based data have demonstrated inferior outcomes to previous series. We examined disease-related outcomes for stage I tumors treated with pancreaticoduodenectomy, with and without CRT.All patients with stage I ampullary adenocarcinoma treated from 1976 to 2011 at Duke University were reviewed. Disease-related endpoints including local control (LC), metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method.Forty-four patients were included in this study. Thirty-one patients underwent surgery alone, while 13 also received adjuvant CRT. Five-year LC, MFS, DFS and OS for patients treated with surgery only and surgery with CRT were 56% and 83% (P=0.13), 67% and 83% (P=0.31), 56% and 83% (P=0.13), and 53% and 68% (P=0.09), respectively.The prognosis for patients diagnosed with stage I ampullary adenocarcinoma may not be as favorable as previously described. Our data suggests a possible benefit of adjuvant CRT delivery.

Authors
Zhong, J; Palta, M; Willett, CG; McCall, SJ; McSherry, F; Tyler, DS; Uronis, HE; Czito, BG
MLA Citation
Zhong, J, Palta, M, Willett, CG, McCall, SJ, McSherry, F, Tyler, DS, Uronis, HE, and Czito, BG. "Patterns of failure for stage I ampulla of Vater adenocarcinoma: a single institutional experience." Journal of gastrointestinal oncology 5.6 (December 2014): 421-427.
PMID
25436120
Source
epmc
Published In
Journal of Gastrointestinal Oncology
Volume
5
Issue
6
Publish Date
2014
Start Page
421
End Page
427
DOI
10.3978/j.issn.2078-6891.2014.084

Q-Probes studies in anatomic pathology: quality improvement through targeted benchmarking.

CONTEXT: The Q-Probes program is a peer-comparison quality assurance service offered by the College of American Pathologists that was created in 1989. OBJECTIVE: To establish national benchmarks around a specific quality metric at a specific point in time in anatomic pathology (AP). DESIGN: Q-Probes are based on a voluntary subscription for an individual study. Hospital-based laboratories in the United States, Canada, and 16 other countries have participated. Approximately one-third of all Q-Probes studies address AP metrics. Each Q-Probes study has a primary quality indicator and additional minor indicators. RESULTS: There have been 52 AP Q-Probes studies addressing process-, outcome-, and structure-related quality assurance issues. These Q-Probes studies often represented the first standardized national benchmark for specific metrics in the disciplines of cytopathology, surgical pathology, and autopsy pathology, and as such have been cited more than 1700 times in peer-reviewed literature. The AP Q-Probes studies that have been repeated over time demonstrate improvement in laboratory performance across an international spectrum. CONCLUSIONS: The Q-Probes program has produced important national benchmarks in AP, addressing preanalytic, analytic, and postanalytic factors in the disciplines of cytopathology, surgical pathology, and autopsy pathology. Q-Probes study data have been published, cited, and used in the creation of laboratory accreditation standards and other national guidelines.

Authors
Tworek, JA; Volmar, KE; McCall, SJ; Bashleben, CP; Howanitz, PJ
MLA Citation
Tworek, JA, Volmar, KE, McCall, SJ, Bashleben, CP, and Howanitz, PJ. "Q-Probes studies in anatomic pathology: quality improvement through targeted benchmarking." Archives of pathology & laboratory medicine 138.9 (September 2014): 1156-1166.
PMID
25171698
Source
epmc
Published In
Archives of Pathology & Laboratory Medicine
Volume
138
Issue
9
Publish Date
2014
Start Page
1156
End Page
1166
DOI
10.5858/arpa.2014-0149-oa

Comprehensive molecular characterization of gastric adenocarcinoma.

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Authors
Cancer Genome Atlas Research Network,
MLA Citation
Cancer Genome Atlas Research Network, . "Comprehensive molecular characterization of gastric adenocarcinoma." Nature 513.7517 (September 2014): 202-209.
PMID
25079317
Source
epmc
Published In
Nature
Volume
513
Issue
7517
Publish Date
2014
Start Page
202
End Page
209
DOI
10.1038/nature13480

Identification and validation of actionable mutations in solid tumors

Authors
Zessin, AS; Randall, A; McCall, S; Datto, MB; Hsu, SD
MLA Citation
Zessin, AS, Randall, A, McCall, S, Datto, MB, and Hsu, SD. "Identification and validation of actionable mutations in solid tumors." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

PURPOSE: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS: Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Invest New Drugs 32.2 (April 2014): 330-339.
PMID
24173967
Source
pubmed
Published In
Invest New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

TTF-1 Is Expressed in a Subset of Esophageal Adenocarcinomas

Authors
Layne, AC; Cummings, TJ; Guy, CD; Cardona, DM; Bentley, RC; Shealy, MJ; Zhang, X; McCall, SJ
MLA Citation
Layne, AC, Cummings, TJ, Guy, CD, Cardona, DM, Bentley, RC, Shealy, MJ, Zhang, X, and McCall, SJ. "TTF-1 Is Expressed in a Subset of Esophageal Adenocarcinomas." February 2014.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
27
Publish Date
2014
Start Page
188A
End Page
188A

TTF-1 Is Expressed in a Subset of Esophageal Adenocarcinomas

Authors
Layne, AC; Cummings, TJ; Guy, CD; Cardona, DM; Bentley, RC; Shealy, MJ; Zhang, X; McCall, SJ
MLA Citation
Layne, AC, Cummings, TJ, Guy, CD, Cardona, DM, Bentley, RC, Shealy, MJ, Zhang, X, and McCall, SJ. "TTF-1 Is Expressed in a Subset of Esophageal Adenocarcinomas." February 2014.
Source
wos-lite
Published In
Laboratory Investigation
Volume
94
Publish Date
2014
Start Page
188A
End Page
188A

Delayed Specimen Collection May Artifactually Damage the Mucosal Surface in Barrett's EMR Specimens

Authors
Zhang, X; Zhao, L; Guy, CD; McCall, SJ; Cardona, DM; Burbridge, RA; Garman, KS; Branch, MS; Siddiqui, U; Xiao, S-Y; Waxman, I; Hart, J
MLA Citation
Zhang, X, Zhao, L, Guy, CD, McCall, SJ, Cardona, DM, Burbridge, RA, Garman, KS, Branch, MS, Siddiqui, U, Xiao, S-Y, Waxman, I, and Hart, J. "Delayed Specimen Collection May Artifactually Damage the Mucosal Surface in Barrett's EMR Specimens." February 2014.
Source
wos-lite
Published In
Laboratory Investigation
Volume
94
Publish Date
2014
Start Page
211A
End Page
211A

Delayed Specimen Collection May Artifactually Damage the Mucosal Surface in Barrett's EMR Specimens

Authors
Zhang, X; Zhao, L; Guy, CD; McCall, SJ; Cardona, DM; Burbridge, RA; Garman, KS; Branch, MS; Siddiqui, U; Xiao, S-Y; Waxman, I; Hart, J
MLA Citation
Zhang, X, Zhao, L, Guy, CD, McCall, SJ, Cardona, DM, Burbridge, RA, Garman, KS, Branch, MS, Siddiqui, U, Xiao, S-Y, Waxman, I, and Hart, J. "Delayed Specimen Collection May Artifactually Damage the Mucosal Surface in Barrett's EMR Specimens." February 2014.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
27
Publish Date
2014
Start Page
211A
End Page
211A

The Role of Eosinophils and Neuroendocrine Cell Nests in the Assessment of Gastrointestinal Biopsies in Bone Marrow Transplant Patients

Authors
Shealy, MJ; de Ridder, GG; McCall, SJ; Guy, CD; Zhang, X; Cardona, DM
MLA Citation
Shealy, MJ, de Ridder, GG, McCall, SJ, Guy, CD, Zhang, X, and Cardona, DM. "The Role of Eosinophils and Neuroendocrine Cell Nests in the Assessment of Gastrointestinal Biopsies in Bone Marrow Transplant Patients." February 2014.
Source
wos-lite
Published In
Laboratory Investigation
Volume
94
Publish Date
2014
Start Page
203A
End Page
203A

The Role of Eosinophils and Neuroendocrine Cell Nests in the Assessment of Gastrointestinal Biopsies in Bone Marrow Transplant Patients

Authors
Shealy, MJ; de Ridder, GG; McCall, SJ; Guy, CD; Zhang, X; Cardona, DM
MLA Citation
Shealy, MJ, de Ridder, GG, McCall, SJ, Guy, CD, Zhang, X, and Cardona, DM. "The Role of Eosinophils and Neuroendocrine Cell Nests in the Assessment of Gastrointestinal Biopsies in Bone Marrow Transplant Patients." February 2014.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
27
Publish Date
2014
Start Page
203A
End Page
203A

Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src act expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (January 1, 2014): 330-339.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Radiosensitive orbital metastasis as presentation of occult colonic adenocarcinoma.

An 82-year-old man presented with progressive right frontal headaches. The patient's history was significant for benign polyps on surveillance colonoscopy 2 years prior, without high-grade dysplasia or carcinoma. MRI revealed an enhancing lesion arising within the superomedial aspect of the right orbit. Lesion biopsy demonstrated histological appearance and immunophenotype suggestive of colonic adenocarcinoma. Staging positron emission tomography/CT showed visceral metastases and diffuse activity in the posterior rectosigmoid, consistent with metastatic colon cancer. Treatment of the orbital lesion with external beam radiotherapy to 30 Gy resulted in significant palliation of the patient's headaches. The patient expired 2 months following treatment completion due to disease progression. Orbital metastasis as the initial presentation of an occult colorectal primary lesion is exceedingly rare, and occurred in this patient despite surveillance colonoscopy. Radiotherapy remains an efficacious modality for treatment of orbital metastases.

Authors
Ludmir, EB; McCall, SJ; Czito, BG; Palta, M
MLA Citation
Ludmir, EB, McCall, SJ, Czito, BG, and Palta, M. "Radiosensitive orbital metastasis as presentation of occult colonic adenocarcinoma." BMJ case reports 2014 (January 2014).
PMID
25240005
Source
epmc
Published In
Bmj Case Reports
Volume
2014
Publish Date
2014
DOI
10.1136/bcr-2014-206407

Patterns of Failure for Stage I Ampulla of Vater Adenocarcinoma: A Single Institutional Experience

Authors
Zhong, J; Palta, M; Willett, CG; McCall, SJ; McSherry, F; Uronis, HE; Tyler, DS; Czito, BG
MLA Citation
Zhong, J, Palta, M, Willett, CG, McCall, SJ, McSherry, F, Uronis, HE, Tyler, DS, and Czito, BG. "Patterns of Failure for Stage I Ampulla of Vater Adenocarcinoma: A Single Institutional Experience." October 2013.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
87
Issue
2
Publish Date
2013
Start Page
S317
End Page
S317
DOI
10.1016/j.ijrobp.2013.06.832

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors

Authors
Strickler, JH; McCall, S; Nixon, AB; Pang, H; Rushing, C; Arrowood, C; Haley, S; Meadows, K; Hurwitz, H
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Pang, H, Rushing, C, Arrowood, C, Haley, S, Meadows, K, and Hurwitz, H. "Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

The role of local excision in invasive adenocarcinoma of the ampulla of Vater.

BACKGROUND: Ampulla of Vater carcinomas are rare malignancies that have been traditionally treated with radical surgical resection. Given the mortality associated with pancreaticoduodenectomy, some patients may benefit from local resection. A single-institution outcomes analysis was performed to define the role of local resection. METHODS: Patients undergoing local resection (ampullectomy) for ampullary carcinomas at Duke University between 1976 and 2010 were analyzed retrospectively. Time-to-event analysis was conducted analyzing all patients undergoing surgery, with and without adjuvant chemoradiation therapy (CRT). Overall survival (OS), local control (LC), metastases-free survival (MFS), and disease-free survival (DFS) were studied using Kaplan-Meier analysis. RESULTS: A total of 17 patients with invasive carcinoma underwent ampullectomy. The 3-and 5-year LC, MFS, DFS and OS rates were 36% and 24%, 68% and 54%, 31% and 21%, and 35% and 21%, respectively. Patients receiving adjuvant CRT did not appear to have improved outcomes compared with surgery alone, although this group tended to have poorer histological grade, more advanced tumor staging and involved surgical margins. CONCLUSIONS: Ampullectomy for invasive ampullary adenocarcinomas is a safe procedure but does not offer satisfactory long-term results, mostly due to high local failure rates. Adjuvant CRT therapy does not appear to offer increased local control or survival benefit following ampullectomy, although these results may suffer from selection bias and small sample size. Local resection should be limited to benign ampullary lesions or patients with very small, early tumors with favorable histologic features where radical resection is not feasible.

Authors
Zhong, J; Palta, M; Willett, CG; McCall, SJ; Bulusu, A; Tyler, DS; White, RR; Uronis, HE; Pappas, TN; Czito, BG
MLA Citation
Zhong, J, Palta, M, Willett, CG, McCall, SJ, Bulusu, A, Tyler, DS, White, RR, Uronis, HE, Pappas, TN, and Czito, BG. "The role of local excision in invasive adenocarcinoma of the ampulla of Vater." J Gastrointest Oncol 4.1 (March 2013): 8-13.
PMID
23450004
Source
pubmed
Published In
Journal of Gastrointestinal Oncology
Volume
4
Issue
1
Publish Date
2013
Start Page
8
End Page
13
DOI
10.3978/j.issn.2078-6891.2012.055

Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is a global health dilemma. The gold standard for diagnosis is liver biopsy. Ballooned hepatocytes are histologic manifestations of hepatocellular injury and are characteristic of steatohepatitis, the more severe form of nonalcoholic fatty liver disease. Definitive histologic identification of ballooned hepatocytes on routine stains, however, can be difficult. Immunohistochemical evidence for loss of the normal hepatocytic keratin 8/18 can serve as an objective marker of ballooned hepatocytes. We sought to explore the utility of a keratin 8/18 plus ubiquitin double immunohistochemical stain for the histologic evaluation of adult nonalcoholic fatty liver disease. Double immunohistochemical staining for keratin 8/18 and ubiquitin was analyzed using 40 adult human nonalcoholic fatty liver disease core liver biopsies. Ballooned hepatocytes lack keratin 8/18 staining as previously shown by others, but normal-size hepatocytes with keratin loss are approximately 5 times greater in number than keratin-negative ballooned hepatocytes. Keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin deposits show a zonal distribution, are positively associated with each other, and are frequently found adjacent to or intermixed with fibrous matrix. All 3 lesions correlate with fibrosis stage and the hematoxylin and eosin diagnosis of steatohepatitis (all P < .05). Compared with hematoxylin and eosin staining, immunohistochemical staining improves the receiver operating characteristics curve for advanced fibrosis (0.77 versus 0.83, 0.89, and 0.89 for keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin, respectively) because immunohistochemistry is more sensitive and specific for fibrogenic hepatocellular injury than hematoxylin and eosin staining. Keratin 8/18 plus ubiquitin double immunohistochemical stain improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Thus, it may help differentiate nonalcoholic steatohepatitis from nonalcoholic fatty liver.

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abdelmalek, MF; Cardona, D; McCall, SJ; Ünalp, A; Belt, P; Ferrell, LD; Diehl, AM; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abdelmalek, MF, Cardona, D, McCall, SJ, Ünalp, A, Belt, P, Ferrell, LD, Diehl, AM, and Nonalcoholic Steatohepatitis Clinical Research Network, . "Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease." Hum Pathol 43.6 (June 2012): 790-800.
PMID
22036053
Source
pubmed
Published In
Human Pathology
Volume
43
Issue
6
Publish Date
2012
Start Page
790
End Page
800
DOI
10.1016/j.humpath.2011.07.007

A phase I/II study of capecitabine (Cape), oxaliplatin (Ox), panitumumab (Pmab), and external beam radiation therapy (RT) for patients with esophagogastric carcinoma (EC).

68 Background: EC is commonly managed with concurrent chemoradiotherapy, with or without surgical resection. The optimal combination and dose of agents is the subject of continued investigation. This study examines chemotherapeutic agents with known efficacy in EC in combination with the EGFR inhibitor panitumumab.Eligible pts received RT (1.8 Gy qd to 50.4 Gy) combined with concurrent chemotherapy. Dose-level (DL) 1 was cape (625 mg/m2/bid RT days), ox (40 mg/m2 weekly X 6 weeks), and pmab (3.6 mg/kg, weeks 1, 3 and 5). Chemotherapy doses were escalated barring dose limiting toxicity (DLT). The primary endpoint was defining the maximally tolerated dose with this combination. Secondary endpoints included toxicity and radiographic/pathologic response rates.Twenty-nine pts were enrolled. Twenty-five had adenocarcinoma, 24 (83%) were cN+ and 9 (31%) had M1a/b disease. DLT was not encountered in DL 1. Two of 6 patients at DL 2 (cape 825 mg/m2/bid RT days, ox 50 mg/m2 weekly, pmab 4.8 mg/kg, weeks 1, 3 and 5) developed DLT (one hospitalization due to dehydration; one with drug reaction requiring hospitalization). Twenty additional pts were enrolled at DL1. Primary toxicities were EGFR-rash, esophagitis, nausea/vomiting and fatigue. On repeat endoscopy, 16 (55%) had CR, 10 (35%) PR and 2 (7%) SD. Using PERCIST criteria, 12 (41%), 11 (38%), 2 (7%) and 3 (10%) had CR, PR, SD and PD response on restaging PET, respectively. Twenty pts underwent esophagectomy, revealing Gr 0 response (no residual disease) in 9 (45%), Gr 1 (single/microscopic cells) in 3 (15%), Gr 2 (fibrosis > gross disease) in 4 (20%) and Gr 3 (gross residual > fibrosis or no evident response) in 4 (20%). Seven pts (35%) experienced anastomotic leak (2 requiring reoperation and 3 stent placement).Concurrent chemoradiotherapy utilizing capecitabine, oxaliplatin, panitumumab is reasonably well-tolerated and associated with high rates of radiographic, endoscopic and pathologic response. Postoperative anastomotic leak rates were higher than expected. Further study of this regimen in the operative and nonoperative settings is warranted.

Authors
Czito, BG; Willett, C; Palta, M; McCall, S; Gee, N; Hurwitz, H; Coleman, RE; Zafar, Y; Kennedy-Newton, P; Uronis, H
MLA Citation
Czito, BG, Willett, C, Palta, M, McCall, S, Gee, N, Hurwitz, H, Coleman, RE, Zafar, Y, Kennedy-Newton, P, and Uronis, H. "A phase I/II study of capecitabine (Cape), oxaliplatin (Ox), panitumumab (Pmab), and external beam radiation therapy (RT) for patients with esophagogastric carcinoma (EC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.4_suppl (February 2012): 68-.
PMID
27982872
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
68

A phase I/II study of capecitabine (Cape), oxaliplatin (Ox), panitumumab (Pmab), and external beam radiation therapy (RT) for patients with esophagogastric carcinoma (EC).

Authors
Czito, BG; Willett, C; Palta, M; McCall, S; Gee, N; Hurwitz, H; Coleman, RE; Zafar, Y; Kennedy-Newton, P; Uronis, H
MLA Citation
Czito, BG, Willett, C, Palta, M, McCall, S, Gee, N, Hurwitz, H, Coleman, RE, Zafar, Y, Kennedy-Newton, P, and Uronis, H. "A phase I/II study of capecitabine (Cape), oxaliplatin (Ox), panitumumab (Pmab), and external beam radiation therapy (RT) for patients with esophagogastric carcinoma (EC)." February 2012.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
68
End Page
68
DOI
10.1200/jco.2012.30.4_suppl.68

Histological and molecular evaluation of patient-derived colorectal cancer explants.

Mouse models have been developed to investigate colorectal cancer etiology and evaluate new anti-cancer therapies. While genetically engineered and carcinogen-induced mouse models have provided important information with regard to the mechanisms underlying the oncogenic process, tumor xenograft models remain the standard for the evaluation of new chemotherapy and targeted drug treatments for clinical use. However, it remains unclear to what extent explanted colorectal tumor tissues retain inherent pathological features over time. In this study, we have generated a panel of 27 patient-derived colorectal cancer explants (PDCCEs) by direct transplantation of human colorectal cancer tissues into NOD-SCID mice. Using this panel, we performed a comparison of histology, gene expression and mutation status between PDCCEs and the original human tissues from which they were derived. Our findings demonstrate that PDCCEs maintain key histological features, basic gene expression patterns and KRAS/BRAF mutation status through multiple passages. Altogether, these findings suggest that PDCCEs maintain similarity to the patient tumor from which they are derived and may have the potential to serve as a reliable preclinical model that can be incorporated into future strategies to optimize individual therapy for patients with colorectal cancer.

Authors
Uronis, JM; Osada, T; McCall, S; Yang, XY; Mantyh, C; Morse, MA; Lyerly, HK; Clary, BM; Hsu, DS
MLA Citation
Uronis, JM, Osada, T, McCall, S, Yang, XY, Mantyh, C, Morse, MA, Lyerly, HK, Clary, BM, and Hsu, DS. "Histological and molecular evaluation of patient-derived colorectal cancer explants." Plos One 7.6 (January 2012): e38422-null.
PMID
22675560
Source
epmc
Published In
Plos One
Volume
7
Issue
6
Publish Date
2012
Start Page
e38422
DOI
10.1371/journal.pone.0038422

Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia.

Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse-transcription polymerase chain reaction (QRT-PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age-matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand-enriched medium ± Hh-neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra- and extrahepatic ductular cells demonstrated striking up-regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh-producing cells and Hh-responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh-responsive. Treating immature ductular cells with Hh ligand-enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this.BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy.

Authors
Omenetti, A; Bass, LM; Anders, RA; Clemente, MG; Francis, H; Guy, CD; McCall, S; Choi, SS; Alpini, G; Schwarz, KB; Diehl, AM; Whitington, PF
MLA Citation
Omenetti, A, Bass, LM, Anders, RA, Clemente, MG, Francis, H, Guy, CD, McCall, S, Choi, SS, Alpini, G, Schwarz, KB, Diehl, AM, and Whitington, PF. "Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia." Hepatology (Baltimore, Md.) 53.4 (April 2011): 1246-1258.
PMID
21480329
Source
epmc
Published In
Hepatology (Baltimore, Md.)
Volume
53
Issue
4
Publish Date
2011
Start Page
1246
End Page
1258
DOI
10.1002/hep.24156

A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abelmalek, MF; Cardona, D; McCall, SJ; Unlap, A; Belt, P; Wilson, L; Ferrell, LD; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abelmalek, MF, Cardona, D, McCall, SJ, Unlap, A, Belt, P, Wilson, L, Ferrell, LD, and Diehl, AM. "A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis." February 2011.
Source
wos-lite
Published In
Laboratory Investigation
Volume
91
Publish Date
2011
Start Page
361A
End Page
361A

A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abelmalek, MF; Cardona, D; McCall, SJ; Unlap, A; Belt, P; Wilson, L; Ferrell, LD; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abelmalek, MF, Cardona, D, McCall, SJ, Unlap, A, Belt, P, Wilson, L, Ferrell, LD, and Diehl, AM. "A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis." February 2011.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
24
Publish Date
2011
Start Page
361A
End Page
361A

Rho GTPase activity modulates Wnt3a/beta-catenin signaling.

Wnt proteins constitute a family of secreted signaling molecules that regulate highly conserved pathways essential for development and, when aberrantly activated, drive oncogenesis in a number of human cancers. A key feature of the most widely studied Wnt signaling cascade is the stabilization of cytosolic beta-catenin, resulting in beta-catenin nuclear translocation and transcriptional activation of multiple target genes. In addition to this canonical, beta-catenin-dependent pathway, Wnt3A has also been shown to stimulate RhoA GTPase. While the importance of activated Rho to non-canonical Wnt signaling is well appreciated, the potential contribution of Wnt3A-stimulated RhoA to canonical beta-catenin-dependent transcription has not been examined and is the focus of this study. We find that activated Rho is required for Wnt3A-stimulated osteoblastic differentiation in C3H10T1/2 mesenchymal stem cells, a biological phenomenon mediated by stabilized beta-catenin. Using expression microarrays and real-time RT-PCR analysis, we show that Wnt3A-stimulated transcription of a subset of target genes is Rho-dependent, indicating that full induction of these Wnt targets requires both beta-catenin and Rho activation. Significantly, neither beta-catenin stabilization nor nuclear translocation stimulated by Wnt3A is affected by inhibition or activation of RhoA. These findings identify Rho activation as a critical element of the canonical Wnt3A-stimulated, beta-catenin-dependent transcriptional program.

Authors
Rossol-Allison, J; Stemmle, LN; Swenson-Fields, KI; Kelly, P; Fields, PE; McCall, SJ; Casey, PJ; Fields, TA
MLA Citation
Rossol-Allison, J, Stemmle, LN, Swenson-Fields, KI, Kelly, P, Fields, PE, McCall, SJ, Casey, PJ, and Fields, TA. "Rho GTPase activity modulates Wnt3a/beta-catenin signaling." Cell Signal 21.11 (November 2009): 1559-1568.
PMID
19482078
Source
pubmed
Published In
Cellular Signalling
Volume
21
Issue
11
Publish Date
2009
Start Page
1559
End Page
1568
DOI
10.1016/j.cellsig.2009.05.010

Analysis of Hepatic Progenitor Populations in Methyl Deficient Liver Injury

Authors
Sicklick, JK; Huang, J; McCall, SJ; Torbenson, MS; Diehl, AM
MLA Citation
Sicklick, JK, Huang, J, McCall, SJ, Torbenson, MS, and Diehl, AM. "Analysis of Hepatic Progenitor Populations in Methyl Deficient Liver Injury." ANNALS OF SURGICAL ONCOLOGY 16 (February 2009): 33-33.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
16
Publish Date
2009
Start Page
33
End Page
33

Fructose consumption as a risk factor for non-alcoholic fatty liver disease.

While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD.A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n=49) without cirrhosis and controls (n=24) matched for gender, age (+/-5 years), and body mass index (+/-3 points).Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p<0.05)]. In patients with NAFLD (n=6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p=0.04 and p=0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity.The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.

Authors
Ouyang, X; Cirillo, P; Sautin, Y; McCall, S; Bruchette, JL; Diehl, AM; Johnson, RJ; Abdelmalek, MF
MLA Citation
Ouyang, X, Cirillo, P, Sautin, Y, McCall, S, Bruchette, JL, Diehl, AM, Johnson, RJ, and Abdelmalek, MF. "Fructose consumption as a risk factor for non-alcoholic fatty liver disease." Journal of Hepatology 48.6 (June 2008): 993-999.
PMID
18395287
Source
epmc
Published In
Journal of Hepatology
Volume
48
Issue
6
Publish Date
2008
Start Page
993
End Page
999
DOI
10.1016/j.jhep.2008.02.011

Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis.

Transient receptor potential subtype vanilloid 1 (TRPV1) is an ion channel that is primarily expressed by primary sensory neurons where it mediates pain and heat sensation and participates in neurogenic inflammation. In this study, we examined the role of TRPV1 during neurogenic activation of pancreatic inflammation using a secretagogue-induced model in mice.A supramaximal dose of caerulein (50 microg/kg) was injected hourly for 12 hours. Mice lacking TRPV1 were compared to wild-type animals.All the parameters: serum amylase, pancreatic myeloperoxidase activity, histological scoring, pancreatic wet weight/body weight ratio, and quantification of neurokinin-1 receptor internalization indicated that null mice were not protected from acute pancreatitis. However, when primary sensory neurons were ablated by injection of the neurotoxin and TRPV1 agonist, resiniferatoxin, pancreatitis was ameliorated in wild-type mice but not in null mice, indicating that nerves bearing TRPV1 are part of the inflammatory pathway in acute pancreatitis because disappearance significantly reduced the inflammatory response.Nerves expressing TRPV1 participate in the neurogenic inflammation during acute pancreatitis. The lack of protection in TRPV1 null mice suggests that an alternate pathway to TRPV1 coexists in the same neurons.

Authors
Romac, JMJ; McCall, SJ; Humphrey, JE; Heo, J; Liddle, RA
MLA Citation
Romac, JMJ, McCall, SJ, Humphrey, JE, Heo, J, and Liddle, RA. "Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis." Pancreas 36.4 (May 2008): 394-401.
PMID
18437086
Source
epmc
Published In
Pancreas
Volume
36
Issue
4
Publish Date
2008
Start Page
394
End Page
401
DOI
10.1097/mpa.0b013e318160222a

Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis.

UNLABELLED: Retinyl ester (RE) stores decrease during hepatic stellate cell (HSC) activation and liver fibrosis. Although retinol esterification is mostly catalyzed by lecithin:retinol acyltransferase (LRAT), diacylglycerol acyltransferase (DGAT)1 also does this. In previous reports, LRAT(-/-) mice had reduced hepatic RE but neither excessive HSC activation nor liver fibrosis, and DGAT1(-/-) mice had increased liver levels of RE and retinol. We sought to clarify the role of DGAT1 in liver fibrosis. Expression of DGAT1/2 was compared by real time PCR in freshly isolated, primary mouse HSCs and hepatocytes. To induce nonalcoholic steatohepatitis (NASH) and liver fibrosis, adult male db/db mice were fed methionine choline-deficient (MCD) diets. Half were treated with DGAT1 antisense oligonucleotide (ASO); the rest were injected with saline. Results were compared with chow-fed controls. Inhibition of DGAT1 in liver had no effect on hepatic triglyceride content or liver necroinflammation but reduced HSC activation and liver fibrosis in mice with NASH. To evaluate the role of DGAT1 in HSC activation, HSC were isolated from healthy rats treated with DGAT1 ASO or saline. DGAT1 was expressed at relatively high levels in HSCs. HSC isolated from DGAT1 ASO-treated rats had reduced DGAT1 expression and increased messenger RNA (mRNA) levels of LRAT and cellular retinol binding protein-1. During culture, they retained more vitamin A, had repressed collagen a2 (I) transcriptional activity, and expressed less collagen a1 (I) and a2 (I) mRNA. CONCLUSION: DGAT1 may be a therapeutic target in NASH because inhibiting DGAT1 favorably altered. HSC retinoid homeostasis and inhibited hepatic fibrosis in mice with NASH.

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis." Hepatology 47.2 (February 2008): 625-635.
PMID
18000880
Source
pubmed
Published In
Hepatology
Volume
47
Issue
2
Publish Date
2008
Start Page
625
End Page
635
DOI
10.1002/hep.21988

Effectiveness of Glycerol Mono-oleate as a Biosealant.

BACKGROUND: The number of femoral artery catheterizations will increase over the next decade to more than 9 million worldwide. Accordingly, a new era of access site management with vascular closure techniques utilizing biologics are being developed and implemented. Glycerol mono-oleate (GMO) is one such biologic - a biodegradable compound that changes from a solid phase to a bioadhesive swollen semisolid phase when exposed to aqueous solutions and heat. We assessed whether GMO would: 1) achieve hemostasis more effectively than control when injected into a swine liver biopsy tract; and 2) inhibit common percutaneous procedure pathogens. METHODS: During the hemostasis experiment, seven swine anticoagulated with heparin (ACT > 250) underwent 10 open-liver biopsies with a 14 gauge cutting needle; 5 injected with GMO (treatment) and 5 injected with nothing (control). Thirty seconds, 2 minutes, 5 minutes and 10 minutes after the procedure, bleeding was objectively graded; 0 = no bleeding (success) and 1 = bleeding (failure). During the bacteria experiment, GMO was injected into plates containing culture media for 4 common percutaneous pathogens (Enteroccocis faecalis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae). When injected, GMO converted to a semisolid phase with definitive margins in the culture media. Each bacterium was then coated over their respective media and GMO. RESULTS: The results showed a significant treatment effect (p < 0.017) on each success/failure bleeding outcome at 30 seconds (p < 0.0001), 2 minutes (p < 0.0001) and 5 minutes (p = 0.0038) based on a multiple logistic regression analysis controlling for initial bleeding, pig and side-of-liver biopsy (medial or lateral lobe). At 10 minutes, the bleeding results were not significant (p = 0.0917), likely explained by a pig's innate ability to clot at this time period. For the bacteria experiment, there was no growth of bacteria on the GMO for any of the plates. Specifically, the Staphylococcus aureus plate displayed a 200 micron halo containing no bacterial growth surrounding the GMO. CONCLUSION: In conclusion, these results illustrate a significant hemostatic effect post liver biopsy at multiple time points using GMO. Furthermore, GMO displays bacterial deterrent properties.

Authors
Adams, GL; Manson, RJ; Giangiacomo, DM; Fronheiser, L; McCall, S; Nightingale, R; Hasselblad, V; Shaw, LK; Milton, L; Lawson, JH
MLA Citation
Adams, GL, Manson, RJ, Giangiacomo, DM, Fronheiser, L, McCall, S, Nightingale, R, Hasselblad, V, Shaw, LK, Milton, L, and Lawson, JH. "Effectiveness of Glycerol Mono-oleate as a Biosealant." J Invasive Cardiol 20.1 (January 2008): 29-34.
PMID
18174616
Source
pubmed
Published In
Journal of Invasive Cardiology
Volume
20
Issue
1
Publish Date
2008
Start Page
29
End Page
34

Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.

UNLABELLED: In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic male db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet-fed mice compared to controls. Treating MCD diet-fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity. CONCLUSION: Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD.

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis." Hepatology (Baltimore, Md.) 45.6 (June 2007): 1366-1374.
PMID
17476695
Source
epmc
Published In
Hepatology (Baltimore, Md.)
Volume
45
Issue
6
Publish Date
2007
Start Page
1366
End Page
1374
DOI
10.1002/hep.21655

Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation.

In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal-epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.

Authors
Omenetti, A; Yang, L; Li, Y-X; McCall, SJ; Jung, Y; Sicklick, JK; Huang, J; Choi, S; Suzuki, A; Diehl, AM
MLA Citation
Omenetti, A, Yang, L, Li, Y-X, McCall, SJ, Jung, Y, Sicklick, JK, Huang, J, Choi, S, Suzuki, A, and Diehl, AM. "Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation." Laboratory Investigation; a Journal of Technical Methods and Pathology 87.5 (May 2007): 499-514.
PMID
17334411
Source
epmc
Published In
Laboratory Investigation
Volume
87
Issue
5
Publish Date
2007
Start Page
499
End Page
514
DOI
10.1038/labinvest.3700537

Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis.

UNLABELLED: Indian Hedgehog (Ihh) regulates tissue morphogenesis. Hedgehog (Hh) activity has been demonstrated in human cholangiocarcinoma and hepatocellular carcinoma lines, and in myofibroblasts and progenitors from adult rodent livers. We evaluated Hh pathway involvement in the response to biliary injury in primary biliary cirrhosis (PBC). Liver sections from 3 PBC patients and 3 controls without liver disease were studied. Immunohistochemistry was used to determine if cells that accumulate in PBC livers express Ihh or Hh-target genes including the Hh-receptor, Patched (Ptc), and the Hh-transcriptional activator glioblastoma (Gli) 2. Positive cells were further identified by costaining for cytokeratin (CK) 19, a biliary marker, or OV6, a hepatic progenitor marker. In all subjects, Gli2 and Ptc expression localized in portal areas. The numbers of Gli2- or Ptc-expressing cells/portal triad were each 10-fold greater in patients with PBC than in controls (P<0.05). In PBC livers, some CK19+ cells coexpressed Gli2 or Ptc. Many stromal fibroblastic cells were also Gli2+. Strong Ihh expression was detected in most bile ductular cells. Scattered stromal cells also expressed Ihh. The number of Ihh+ cells/portal triad was 6-fold greater in PBC livers than controls (P<0.05). OV6+ progenitors increased significantly in PBC livers, and some of these cells coexpressed Ihh, Ptc, and/or Gli2. CONCLUSION: This is the first direct evidence that noncancerous, adult human livers harbor several types of cells that produce and/or respond to Hh ligands. Such Hh-responsive cells accumulate during the fibroproliferative response to chronic cholestatic liver injury, suggesting a role for Hh signaling in this process.

Authors
Jung, Y; McCall, SJ; Li, Y-X; Diehl, AM
MLA Citation
Jung, Y, McCall, SJ, Li, Y-X, and Diehl, AM. "Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis." Hepatology 45.5 (May 2007): 1091-1096.
PMID
17464985
Source
pubmed
Published In
Hepatology (Baltimore, Md.)
Volume
45
Issue
5
Publish Date
2007
Start Page
1091
End Page
1096
DOI
10.1002/hep.21660

Qualitative and quantitative differences in response to liver injury in OB/OB mice

Authors
Fleig, SV; Yang, L; Huang, J; Mccall, SJ; Jung, Y; Vandongen, HM; Omenetti, A; Sicklick, JK; Li, Y-X; Diehl, AM
MLA Citation
Fleig, SV, Yang, L, Huang, J, Mccall, SJ, Jung, Y, Vandongen, HM, Omenetti, A, Sicklick, JK, Li, Y-X, and Diehl, AM. "Qualitative and quantitative differences in response to liver injury in OB/OB mice." April 2007.
Source
wos-lite
Published In
Gastroenterology
Volume
132
Issue
4
Publish Date
2007
Start Page
A818
End Page
A818

Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin.

Defects in renal proximal tubule transport manifest in a number of human diseases. Although variable in clinical presentation, disorders such as Hartnup disease, Dent's disease, and Fanconi syndrome are characterized by wasting of solutes commonly recovered by the proximal tubule. One common feature of these disorders is aminoaciduria. There are distinct classes of amino acid transporters located in the apical and basal membranes of the proximal tubules that reabsorb >95% of filtered amino acids, yet few details are known about their regulation. We present our physiological characterization of a mouse line with targeted deletion of the gene collectrin that is highly expressed in the kidney. Collectrin-deficient mice display a reduced urinary concentrating capacity due to enhanced solute clearance resulting from profound aminoaciduria. The aminoaciduria is generalized, characterized by loss of nearly every amino acid, and results in marked crystalluria. Furthermore, in the kidney, collectrin-deficient mice have decreased plasma membrane populations of amino acid transporter subtypes B(0)AT1, rBAT, and b(0,+)AT, as well as altered cellular distribution of EAAC1. Our data suggest that collectrin is a novel mediator of renal amino acid transport and may provide further insight into the pathogenesis of a number of human disease correlates.

Authors
Malakauskas, SM; Quan, H; Fields, TA; McCall, SJ; Yu, M-J; Kourany, WM; Frey, CW; Le, TH
MLA Citation
Malakauskas, SM, Quan, H, Fields, TA, McCall, SJ, Yu, M-J, Kourany, WM, Frey, CW, and Le, TH. "Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin." American Journal of Physiology Renal Physiology 292.2 (February 2007): F533-F544.
PMID
16985211
Source
epmc
Published In
American Journal of Physiology. Renal Physiology
Volume
292
Issue
2
Publish Date
2007
Start Page
F533
End Page
F544
DOI
10.1152/ajprenal.00325.2006

Evidence for epithelial-mesenchymal transitions in adult liver cells.

Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.

Authors
Sicklick, JK; Choi, SS; Bustamante, M; McCall, SJ; Pérez, EH; Huang, J; Li, Y-X; Rojkind, M; Diehl, AM
MLA Citation
Sicklick, JK, Choi, SS, Bustamante, M, McCall, SJ, Pérez, EH, Huang, J, Li, Y-X, Rojkind, M, and Diehl, AM. "Evidence for epithelial-mesenchymal transitions in adult liver cells." American Journal of Physiology. Gastrointestinal and Liver Physiology 291.4 (October 2006): G575-G583.
PMID
16710052
Source
epmc
Published In
American Journal of Physiology Gastrointestinal and Liver Physiology
Volume
291
Issue
4
Publish Date
2006
Start Page
G575
End Page
G583
DOI
10.1152/ajpgi.00102.2006

DGAT2 aso treatment improves hepatic steatosis, but not fibrosis in DB/DB mice fed methionine choline deficient diets

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Hanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Hanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "DGAT2 aso treatment improves hepatic steatosis, but not fibrosis in DB/DB mice fed methionine choline deficient diets." October 2006.
Source
wos-lite
Published In
Hepatology (Baltimore, Md.)
Volume
44
Issue
4
Publish Date
2006
Start Page
665A
End Page
665A

DGAT1 ASO treatment reduces hepatic fibrosis without improving hepatic steatosis in DB/DB mice fed methionine choline deficient diets

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "DGAT1 ASO treatment reduces hepatic fibrosis without improving hepatic steatosis in DB/DB mice fed methionine choline deficient diets." October 2006.
Source
wos-lite
Published In
Hepatology (Baltimore, Md.)
Volume
44
Issue
4
Publish Date
2006
Start Page
663A
End Page
663A

Development and cardiac contractility: cardiac troponin T isoforms and cytosolic calcium in rabbit.

Cardiac contractility depends on calcium sensitivity of the myofilaments and cytosolic free calcium concentration ([Ca(2+)](i)) during activation. During development, the cardiac troponin T isoform cTnT(1) is replaced by shorter cTnT isoforms, including cTnT(4), and changes occur in other myofibrillar proteins and in calcium regulation. We expressed rabbit recombinant (r)cTnT(1) and rcTnT(4) in Spodoptera frugiperda cells and determined their effect on calcium binding to TnC in solution and on the calcium sensitivity of myofilaments in skinned rabbit ventricular fibers in vitro. We measured [Ca(2+)](i) and L-type calcium current (I(Ca)) in ventricular myocytes from 3-wk-old and adult rabbits. The dissociation constant (K(d)) of Ca-Tn(cTnT1) in solution was smaller than that of Ca-Tn(cTnT4) (mean +/- SE: 0.52 +/- 0.08 mumol/L versus 0.83 +/- 0.09 mumol/L). The Ca(2+) sensitivity of force development was greater in fibers reconstituted with rcTnT(1) (pCa(50) 6.07 +/- 0.04) than those reconstituted with rcTnT(4) (pCa(50) 5.75 +/- 0.07). Systolic [Ca](i) was lower in 3-wk-old than adult cells (443 +/- 35 nmol/L versus 882 +/- 88 nmol/L) as was I(Ca) (5.8 +/- 0.9 pA/pF versus 14.2 +/- 1.6 pA/pF). The higher calcium sensitivity of Tn-Ca binding and of force development conferred by rcTnT(1) suggest that higher neonatal cTnT(1) expression may partially compensate for the lower systolic [Ca(2+)](i).

Authors
McCall, SJ; Nassar, R; Malouf, NN; Saunders, AJ; Oakeley, AE; Henderson, PM; Solaro, RJ; Pielak, GJ; Alexander, KA; Anderson, PAW
MLA Citation
McCall, SJ, Nassar, R, Malouf, NN, Saunders, AJ, Oakeley, AE, Henderson, PM, Solaro, RJ, Pielak, GJ, Alexander, KA, and Anderson, PAW. "Development and cardiac contractility: cardiac troponin T isoforms and cytosolic calcium in rabbit." Pediatric Research 60.3 (September 2006): 276-281.
PMID
16857772
Source
epmc
Published In
Pediatric Research
Volume
60
Issue
3
Publish Date
2006
Start Page
276
End Page
281
DOI
10.1203/01.pdr.0000233004.95404.1f

Interleukin-15 increases hepatic regenerative activity.

BACKGROUND/AIMS: Interleukin-15 (IL-15) is expressed in many organs. It generally inhibits apoptosis and increases cellular proliferation and differentiation. However, IL-15's roles in liver are unknown. We aimed to determine if IL-15 influences hepatic integrity and regenerative activity. METHODS: Expression of IL-15 and its receptors was evaluated in several liver injury models, primary hepatocytes, and two liver cell lines. Effects of IL-15 on viability, proliferation, and apoptosis were assessed in cultured liver cells, and also in the livers of healthy mice. RESULTS: IL-15 and its receptors are expressed constitutively in healthy livers, and ligand expression is induced in injured livers. Cultured primary hepatocytes and liver cell lines express IL-15 and its receptors. Administration of IL-15 has minimal effects on cultured liver cells, but significantly up-regulates oval cell accumulation, cyclin mRNA expression, and mature hepatocyte replication in healthy mice. These effects are associated with focal hepatic inflammation and increased expression of TNF-alpha and IFN-gamma, but not with increased cell death or aminotransferase release. CONCLUSIONS: IL-15 expression increases during liver injury and IL-15 treatment induces a wound healing-type response in healthy adult mice. These findings suggest that IL-15 may contribute to regenerative activity in damaged liver.

Authors
Suzuki, A; McCall, S; Choi, SS; Sicklick, JK; Huang, J; Qi, Y; Zdanowicz, M; Camp, T; Li, Y-X; Diehl, AM
MLA Citation
Suzuki, A, McCall, S, Choi, SS, Sicklick, JK, Huang, J, Qi, Y, Zdanowicz, M, Camp, T, Li, Y-X, and Diehl, AM. "Interleukin-15 increases hepatic regenerative activity." Journal of Hepatology 45.3 (September 2006): 410-418.
PMID
16781000
Source
epmc
Published In
Journal of Hepatology
Volume
45
Issue
3
Publish Date
2006
Start Page
410
End Page
418
DOI
10.1016/j.jhep.2006.04.008

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer.

BACKGROUND: The genetic events leading to initiation and/or progression of prostate cancer are not well characterized. The gene coding for the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) has recently been identified as a tumor suppressor in several types of cancer. The purpose of the present study is to determine whether the M6P/IGF2R gene is inactivated in human prostate cancer, and if so, whether this is an early or late transformational event. METHODS: In total, 43 patients with prostate cancer treated by radical prostatectomy, with archival material available for analysis, were assessed for loss of heterozygosity (LOH) in the M6P/IGF2R gene using six different gene-specific nucleotide polymorphisms. Regions of tumor, normal prostate and premalignant high-grade prostate intraepithelial neoplasia (PIN) were identified and cells were excised by laser capture microdissection (LCM). DNA segments were amplified using polymerase chain reaction (PCR). RESULTS: The M6P/IGF2R gene was polymorphic in 83.7% (36/43) of patients, and 41.7% (15/36) of these informative patients had LOH in the tumor tissue. In 11/15 patients with LOH in malignant tissue, high-grade PIN could be identified, and 63.6% (7/11) also had LOH in this premalignant tissue. CONCLUSIONS: This study is the first to find that the M6P/IGF2R gene is inactivated in prostate cancer. LOH in premalignant tissue as well suggests that mutation in the M6P/IGF2R gene is an early event in the development of prostate cancer, supporting the conclusion that it functions as a tumor suppressor gene in this disease.

Authors
Hu, CK; McCall, S; Madden, J; Huang, H; Clough, R; Jirtle, RL; Anscher, MS
MLA Citation
Hu, CK, McCall, S, Madden, J, Huang, H, Clough, R, Jirtle, RL, and Anscher, MS. "Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer." Prostate Cancer Prostatic Dis 9.1 (2006): 62-67.
PMID
16304558
Source
pubmed
Published In
Prostate Cancer and Prostatic Diseases
Volume
9
Issue
1
Publish Date
2006
Start Page
62
End Page
67
DOI
10.1038/sj.pcan.4500842

IL-15 increases regenerative activity in the livers

Authors
Suzuki, A; McCall, S; Huang, JW; Qi, Y; Zdanowicz, M; Sicklick, J; Camp, T; Li, YX; Diehl, AME
MLA Citation
Suzuki, A, McCall, S, Huang, JW, Qi, Y, Zdanowicz, M, Sicklick, J, Camp, T, Li, YX, and Diehl, AME. "IL-15 increases regenerative activity in the livers." October 2005.
Source
wos-lite
Published In
Hepatology (Baltimore, Md.)
Volume
42
Issue
4
Publish Date
2005
Start Page
572A
End Page
572A

Pulmonary embolization of microcrystalline cellulose in a lung transplant recipient.

Intravenous injection of drugs that contain insoluble foreign material can lead to pulmonary embolization of the material and can have devastating results, including pulmonary hypertension and death. Most cases are detected after the onset of extensive, irreversible damage, precluding potentially life-saving intervention, or are detected at autopsy. We report here a case of microcrystalline cellulose embolization in a lung transplant recipient detected at routine transbronchial biopsy, and we describe the circumstances associated with the development of this condition and its clinical outcome.

Authors
Fields, TA; McCall, SJ; Reams, BD; Roggli, VL; Palmer, SM; Howell, DN
MLA Citation
Fields, TA, McCall, SJ, Reams, BD, Roggli, VL, Palmer, SM, and Howell, DN. "Pulmonary embolization of microcrystalline cellulose in a lung transplant recipient." The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation 24.5 (May 2005): 624-627.
PMID
15896764
Source
epmc
Published In
Journal of Heart and Lung Transplantation
Volume
24
Issue
5
Publish Date
2005
Start Page
624
End Page
627
DOI
10.1016/j.healun.2004.01.023

Loss of heterozygosity in the M6P/IFG2R gene is an early event in the development of prostate cancer

Authors
HU, C; MCCALL, S; MADDEN, J; HUANG, H; CLOUGH, R; RABBANI, Z; JIRTLE, R; ANSCHER, M
MLA Citation
HU, C, MCCALL, S, MADDEN, J, HUANG, H, CLOUGH, R, RABBANI, Z, JIRTLE, R, and ANSCHER, M. "Loss of heterozygosity in the M6P/IFG2R gene is an early event in the development of prostate cancer." September 2004.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
60
Publish Date
2004
Start Page
S460
End Page
S460
DOI
10.1016/S0360-3016(04)01675-X

Prognostic significance of microvascular thrombosis in donor kidney allograft biopsies.

BACKGROUND: With a continuing demand for donor kidneys for organ transplantation, it is important to understand the significance of pathologic findings in the donor organ before transplantation. Microvascular thrombosis is sometimes encountered in association with disseminated intravascular coagulation in the donor, and it is unclear whether this finding may affect immediate allograft function and long-term graft survival. To further elucidate this question, we examined our experience with microvascular thrombosis in donor biopsies in the kidney transplant program at our institution. METHODS: Donor kidney biopsies showing microvascular thrombosis were identified from consecutive donor biopsies in the Duke University Medical Center transplant file database between January 1, 1995 and December 31, 2000. These biopsies and all other kidney biopsies and specimens from the recipients of these kidneys thus identified were reviewed. Sections were stained using a variety of methods, including hematoxylin-eosin, periodic acid-Schiff, methenamine silver, and Masson trichrome methods. Clinical records of the transplant recipients of these kidneys were also reviewed to assess allograft performance and survival. RESULTS: From 230 consecutive donor kidney biopsies, we identified eight cases exhibiting donor-microvascular thrombosis. Mean follow-up times were 27.5 months for the thrombi group and 35 months for the non-thrombi group. Recipients of grafts with donor thrombi were more likely to exhibit delayed graft function, but graft function at 1 and 2 years and graft survival were similar between the two groups. Subsequent posttransplantation biopsies in five of eight cases showed no evidence of residual thrombosis. CONCLUSIONS: These data suggest that the presence of donor microvascular thrombosis does not portend poor outcome in renal transplantation.

Authors
McCall, SJ; Tuttle-Newhall, JE; Howell, DN; Fields, TA
MLA Citation
McCall, SJ, Tuttle-Newhall, JE, Howell, DN, and Fields, TA. "Prognostic significance of microvascular thrombosis in donor kidney allograft biopsies." Transplantation 75.11 (June 15, 2003): 1847-1852.
PMID
12811244
Source
pubmed
Published In
Transplantation
Volume
75
Issue
11
Publish Date
2003
Start Page
1847
End Page
1852
DOI
10.1097/01.TP.0000063126.88887.68

Hepatic veno-occlusive disease in primary humoral immunodeficiency

Authors
McCall, SJ; Myers, LA; Treem, WR; Patel, DD; Gottfried, MR
MLA Citation
McCall, SJ, Myers, LA, Treem, WR, Patel, DD, and Gottfried, MR. "Hepatic veno-occlusive disease in primary humoral immunodeficiency." January 2003.
Source
wos-lite
Published In
Laboratory Investigation
Volume
83
Issue
1
Publish Date
2003
Start Page
281A
End Page
281A

Hepatic veno-occlusive disease in primary humoral immunodeficiency

Authors
McCall, SJ; Myers, LA; Treem, WR; Patel, DD; Gottfried, MR
MLA Citation
McCall, SJ, Myers, LA, Treem, WR, Patel, DD, and Gottfried, MR. "Hepatic veno-occlusive disease in primary humoral immunodeficiency." January 2003.
Source
wos-lite
Published In
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
Volume
16
Issue
1
Publish Date
2003
Start Page
281A
End Page
281A
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Research Areas:

  • Ampulla of Vater
  • Apoptosis
  • Bevacizumab
  • Bile Ducts
  • Biological Markers
  • Biopsy
  • Biopsy, Needle
  • Cell Differentiation
  • Cell Line
  • Cell Nucleus
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Colorectal Neoplasms
  • Colorectal Neoplasms, Hereditary Nonpolyposis
  • Cytochrome P-450 CYP2E1
  • Endocytosis
  • Epithelial Cells
  • Epithelial-Mesenchymal Transition
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Humans
  • Hydroxyproline
  • Immunohistochemistry
  • Kruppel-Like Transcription Factors
  • Lasers
  • Mesenchymal Stromal Cells
  • Mesoderm
  • Microdissection
  • Mutation
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Oligoribonucleotides, Antisense
  • Oncogenes
  • Organoplatinum Compounds
  • Pancreaticoduodenectomy
  • Pancreatitis
  • Pilot Projects
  • Prognosis
  • Protein Isoforms
  • Proteome
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf
  • Pyrimidines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Stromal Cells
  • Thiazoles
  • Tissue Donors
  • Tumor Markers, Biological
  • Tumor Necrosis Factor-alpha
  • Wnt Proteins
  • Xenograft Model Antitumor Assays
  • ras Proteins