by Julie Poucher Harbin (Duke Cancer Institute) and Jamie Miyares Botta (Duke Pathology)
The Duke BioRepository & Precision Pathology Center (BRPC), a clinical research and discovery Shared Resource with its administrative home in the Department of Pathology, was launched in 2012 with a five-year three-million-dollar investment from Duke Cancer Institute and the Duke University School of Medicine. Spurred by key investments in technology, services, and personnel, the BRPC grew, thrived, and progressively built a national reputation.
“It’s success,” notes BRPC director and DCI pathologist Shannon McCall, MD, “represents the evolution and extension of the Department of Pathology’s support and commitment to cancer research.”
The BRPC has served as the biospecimen/pathology core for several U.S. government-funded, multi-institutional, and homegrown studies at Duke Cancer Institute (DCI).
The inclusion of at least one core, McCall notes, and often more than one core, is required for large program-level government grants.
McCall herself is American Board of Pathology-certified in Clinical Informatics as well as Anatomic/Clinical Pathology and General Pathology and is chair of the Biorepository Accreditation Program Committee of the College of American Pathologists. She has been involved in numerous translational cancer research projects that rely on the study of human biological samples and data-driven research. With a research focus on upper GI tract carcinogenesis, she previously served as a member of the data analysis working group for The Cancer Genome Atlas (TCGA) esophageal and pan-GI projects.
Under McCall's leadership, DCI joined a national molecular registry of tumors — the American Association for Cancer Research's PROJECT GENIE (Genomics Evidence Neoplasia Information Exchange) — and became the base for the National Cancer Institute-supported Southern Division of the Cooperative Human Tissue Network.
Leading cancer pathologists with the BRPC, like McCall, have worked and continue to work hand in glove with other DCI investigators on several major cancer research grants, which are described below.
Some Notable Projects
Duke BRPC: New Site of CHTN Southern Division (click to open or close)
The BRPC has served as the base for the NCI-supported Southern Division of the Cooperative Human Tissue Network since 2019. Shannon McCall, MD, director of the BRPC is principal investigator on the $3.4 million, five-year grant.
The CHTN was established in 1987 to increase access, for investigators, to human tissue and tissue processing services in order to accelerate the pace of cancer research.
PROJECT GENIE (click to open or close)
For more than three years, Duke Cancer Institute has been sharing its genomic data (de-identified) from its own molecular registry of tumors — Frameshift MRT — with an international pan-cancer molecular registry of tumors: the American Association of Cancer Research’s PROJECT GENIE (Genomics Evidence Neoplasia Information Exchange).
Like Frameshift MRT, GENIE uses real-world data to uncover driver mutations of cancer subtypes, including in rare tumors, identify cancer types with and without actionable (druggable) mutations, and evaluate genome-guided clinical trial design.
Founded in late 2015, the latest public release (GENIE 9.1) contains data from more than 110,000 tumors from more than 100,000 patients, which is used by researchers worldwide for the global good of cancer research and care. There are now 19 cancer centers, including DCI, in the U.S., Canada, the United Kingdom, France, the Netherlands, and Spain pooling their data into GENIE.
Shannon McCall, MD, Duke site PI for GENIE, and her team of BRPC experts in histopathologic and molecular data annotation, partnered with Michael Datto, MD, PhD, Chris Hubbard, computer programmers Jeremy Gresham and Michael Fox, and Kouros Owzar, PhD, (director of the DCI Bioinformatics Shared Resource), to prepare the first annual batch of 500 NGS test records for GENIE in 2018. Duke Cancer Institute has so far contributed de-identified genomic sequencing data from more than 2,600 patients to GENIE.
McCall is also a member of the GENIE Steering Committee.
Michelle Green, PhD, is Duke’s representative on the GENIE analytical working group.
Learn More about PROJECT GENIE
AACR Project GENIE: 100,000 Cases and Beyond Cancer Discovery Sept. 2022 Trevor J. Pugh; Jonathan L. Bell; Jeff P. Bruce; Gary J. Doherty; Matthew Galvin; Michelle F. Green; Haley Hunter-Zinck; Priti Kumari; Michele L. Lenoue-Newton; Marilyn M. Li; James Lindsay; Tali Mazor; Andrea Ovalle; Stephen-John Sammut; Nikolaus Schultz; Thomas V. Yu; Shawn M. Sweeney; Brady Bernard; for the AACR Project GENIE Consortium, Genomics and Analysis Working Group.
*Duke authors, including Molecular Tumor Board senior research program leader Michelle Green, PhD, and biostatistician Jonathan Bell have been bolded. Green did the actionability analysis in Fig. 5 of this paper
Learn More about Frameshift MRT
Digital Spatial Profiling in Breast Pre-Cancer (click to open or close)
Jadee Neff, MD, PhD, associate director for Genomics, BRPC, oversees the Digital Spatial Profiling service and has used the Nanostring GeoMx Digital Spatial Profiler (DSP), acquired in 2020, to produce a large amount of data in support of the National Cancer Institute Breast Pre-Cancer Atlas (part of the NCI Human Tumor Atlas Network Consortium) — a large national study to determine the benefits of treatment versus watchful waiting for so-called stage 0 breast cancer (ductal carcinoma in situ -- DCIS).
The cross-institutional DCIS molecular mapping initiative is co-led by Shelley Hwang, MD, MHS — vice-chair of research in the Duke Department of Surgery, director of DCI’s Breast Cancer Disease Group, and a member of the NCI-designated DCI Cancer Risk, Detection, and Interception Research Program (CRDI) steering committee — as well as Rob West, MD, PhD (Stanford University) and Carlo Maley, PhD, MSc (Arizona State University).
On November 18, 2022, Hwang and West, with co-investigator Maley, announced, in the journal Cancer Cell, a major advance toward distinguishing whether the early pre-cancers in the breast will develop into invasive cancers or remain stable. Analyzing samples from patients who had undergone surgery to remove areas of DCIS, the team identified 812 genes associated with recurrence within five years from treatment. Using this gene classifier, they were then able to predict both recurrence and invasive progression of cancer, with progression appearing to be dependent on a process that requires interactions between invasive DCIS cells and the unique features of the tumor environment.
The Nanostring GeoMx DSP can quantify the expression of up to 100 proteins or up to 18,000 genes (whole transcriptome analysis) with in situ spatial resolution. Users can comparatively analyze gene expression patterns in single cells or specific regions throughout the tissue specimen on a single slide.
“Spatial profiling technology is game-changing in that it allows us to attribute complex molecular data to specific populations of cells that we identify on a slide,” explains Neff.
In fact, this technology was named 2020 "Method of the Year" by the journal Nature Methods.
Learn more about the Breast Pre-Cancer Atlas project in the Duke Health News November 2022 feature "Newly Developed Gene Classifier Identifies Risk of Breast Pre-Cancer Progression"; in the August 2022 School of Medicine Magnify feature "Mission: Interception — Creating Better Ways to Stop Cancer in Its Tracks;" and here.
Digital Spatial Profiling in Pancreatic Pre-Cancer (click to open or close)
General Surgery resident Austin Eckhoff, MD (see video below), has spent two years performing research in the Allen Pancreatic Cancer Research Lab, under the direction of Peter Allen, MD, PhD (chief of the Division of Surgical Oncology), on intraductal papillary mucinous neoplasms — pancreatic cysts that account for pancreatic cancer cases 20% of the time.
Pancreatic cancer has a dismal prognosis with an overall 5-year survival rate of 11.5% and is rarely diagnosed in the early stages.
Eckhoff and Chanjuan Shi, MD, PhD, chief of the Gastrointestinal Pathology Service, used the Nanostring GeoMx Digital Spatial Profiler to more precisely grade the pancreatic cysts and assess their potential to turn into cancer. Pancreatic cysts are very heterogenous — meaning that areas of high-grade and areas of low-grade dysplasia are often less than 1mm apart and dispersed throughout the entire cyst. This has made past efforts to describe the local immune response and genetic alterations in these cysts (intraductal papillary mucinous neoplasms) difficult.
“An advantage of the Digital Spatial Profiling system is that it allows for the areas of high-grade and low-grade dysplasia to be separately analyzed, giving a better understanding of what is truly driving these cysts towards malignancy,” explains Eckhoff.
In two Annals of Surgical Oncology articles this summer, Eckoff, Allen, Shi, and other DCI faculty published on their team’s early research findings as well as on their work with the pathology technology in advancing their pancreatic research.
Learn more about this project in the August 2022 School of Medicine Magnify feature "Mission: Interception — Creating Better Ways to Stop Cancer in Its Tracks" and in the DCI Blog feature "Allen Leads NIH-Funded Pancreatic Cancer Prevention Trial"
Spatial Transcriptomics in Action
⇒Tissue slides are cut and incubated with both fluorescent antibodies and short probes that bind to specific mRNA sequences within each gene ⇒These probes are coupled to DNA barcodes that are cleavable by UV light ⇒Slides are loaded into the Digital Spatial Profiling instrument, regions of interest (ROIs) are selected, and UV light precisely cleaves the RNA/DNA probes within the specified area ⇒ These probes are dispensed in a microwell plate and sequenced, allowing for gene expression to be mapped back to each region of interest.
Immune Profiling in Stomach Cancer: A Cancer Disparities Project (click to open or close)
Avani Pendse, MD, PhD, associate director for Immunohistochemistry as well as associate director for Proteomics, BRPC, has developed multiplexed colorimetric immunohistochemistry panels for immune profiling in stomach cancer. William Jeck, MD, PhD, DCI member and associate director for Artificial Intelligence & Computational Pathology, BRPC, is building computer code to analyze those panels.
Pendse and Jeck have partnered mainly with Katherine Garman, MD, MHS — co-leader of the stomach cancer disparities subproject of a $3.5M National Cancer Institute-funded DCI project investigating health disparities in stomach and lung cancer and co-director of the NCI-designated DCI Cancer Risk, Detection, and Interception Research Program (CRDI).
The three-year NCI Specialized Program of Research Excellence (SPORE) Grant commenced in 2020. Steven Patierno, PhD, deputy director of DCI and co-leader of the Patierno/Freedman/George Lab is the overall principal investigator.
“Lack of diversity in bio-banking is an Achilles heel to advances in precision oncology – molecular analysis of tumor samples from a diversity of patients is crucial to equitable translation of cancer medicine," says Patierno, who for more than a decade has overseen programs that advance DCI’s mission to eliminate cancer disparities and achieve health equity in the community, and whose research focuses on the molecular biology of cancer disparities, molecular pharmacology, and targeted experimental therapeutics. "The Duke BRPC is at the forefront of being purposeful and deliberate to diversifying its biobank."
Learn more about this project in the August 2022 School of Medicine Magnify feature "Mission: Interception — Creating Better Ways to Stop Cancer in Its Tracks" and in the DCI Breakthroughs magazine feature "About Time."
A Senescent Cell Human Tissue Mapping Center (click to open or close)
Duke Cancer Institute member Carolyn Glass, MD, PhD, joined the BRPC in 2019 as a liaison to the Autopsy and Thoracic Surgical Pathology Service.
In 2021, she began serving as the BRPC liaison to the NCI-designated DCI Immuno-Oncology Research Program. That year she was awarded a five-year $3.2M grant to serve as principal investigator and lead of the Pathology Core for a larger grant ($13.5M) to Duke from the National Institutes of Health/National Institute of Aging to establish a Senescent Cell Human Tissue Mapping Center at Duke — part of the NIH Cellular Senescence Network.
The mission of the NIH Network is to better characterize the role that senescent cells (a rare type of cells) play in human biology — including cancer and degenerative disorders — and to provide a map of normal cellular processes that go awry during the human lifespan.
Other Duke partners on the Senescent Cell Human Tissue Mapping Center project (there are five core leads) include DCI member Andrew Nixon, PhD, MBA, core lead for the Carolina Organ Donor Services, Biological Analysis Core.
Learn more about this project on the Duke Pathology website.
Though by no means a requirement for collaborative research efforts, many faculty who have their primary appointment in the Department of Pathology are either full or associate DCI members, including: Soman Abraham, PhD, Rami Al-Rohil, MBBS, PhD, Rex Bentley, MD, Ming Chen, PhD, Zhong Chen, PhD, Thomas Cummings, MD, Michael Datto, MD, PhD, Jeffrey Everitt, DVM, Rachel Factor, MD, Carolyn Glass, MD, PhD, Yiping He, PhD, Jiaoti Huang, MD, PhD (Department of Pathology Chair), Xiaoyin “Sara” Jiang, MD, William Jeck, MD, PhD, Anand Lagoo, MD, PhD, Chelsea Landon, DVM, PhD, Giselle López, MD, PhD, Everardo Macias, PhD, Shannon McCall, MD, Roger McLendon, MD, Jadee Neff, MD, PhD, Mikhail Nikiforov, PhD, Jung Wook Park, PhD, Beth Shaz, MD, Chanjuan Shi, MD, PhD, Kyle Strickland, MD, PhD, Qianben Wang, PhD, Zijun Xu-Monette, PhD, and Ken Young, MD, PhD.
“There are many benefits to DCI membership for faculty, including enhanced opportunities for collaborative research efforts, access to DCI educational and administrative resources, and the opportunity to apply for DCI Pilot Award funds,” says McCall, who, in addition to directing the BRPC and serving as vice chair of Translational Research in the Pathology Department, also co-leads the NCI-designated DCI Precision Cancer Medicine & Investigational Therapeutics Research Program. “I’m excited about a future where our Pathology faculty have even more opportunities to lead initiatives and projects in support of cancer research.”
This year Duke Cancer Institute commemorates 50 years of cancer care and research as a National Cancer Institute-designated Comprehensive Cancer Center. (1972 — )
Read More of this Special Report
In 2012, Duke Cancer Institute and the Duke University School of Medicine committed to a five-year, three-million-dollar investment in a new Duke BioRepository and Precision Pathology Center (BRPC) — a clinical research and discovery resource with its administrative home in the Department of Pathology. Spurred by key investments in technology, services, and personnel, the BRPC grew, thrived, and progressively built a national reputation. READ
Learn how the Precision Cancer Medicine Initiative is advancing research, extending lives, and breaking down barriers to access. READ
Learn about new developments at the DUHS Clinical Labs' Clinical Molecular Diagnostics Laboratory (MDL). READ