Cancer is a disease of disordered genetic and epigenetic regulation. It starts and progresses via the acquisition of changes in the genome that result in the acquisition of the malignant phenotype. The Cancer Genetics and Genomics (CGG) program serves to coordinate the Duke Cancer Institute (DCI) research activities related to the study and understanding of cancer genetics, epigenetics, gene expression, and genomics, as well as the application of 'omics' technologies that assess alterations in cancer genomes, epigenomes and transcriptomes. The program serves as the primary source of expertise in the DCI for these aspects of cancer.
The CGG program features enhanced interactions among program investigators and with investigators of other programs. Importantly CGG encourages strong interactions between its members and those of clinical programs as a route to translate the basic science findings obtained by the CGG program.
The CGG program supports genomic resources for the DCI: Genomics encompasses a set of enabling high throughput methods that enable the work of researchers throughout the DCI. A particular strength of the CGG program is the genomics expertise that resides in the program. Several members, including Drs. Dave, Hsu, Dressman, Owzar, Katsanis, and Gregory are highly experienced in cancer genomics and have broad collaborations within the program and with other programs that enable the DCI community to use these cutting edge tools. Thus, genomics expertise is disseminated to all DCI members through the focus groups and program-wide activities.
The program is led by Drs. Sandeep Dave and Mariano A. Garcia-Blanco (Co-Directors). Drs. Dave and Garcia-Blanco organize all program wide activities. In close collaboration with Dr. Kastan, Drs. Dave and Garcia-Blanco have re-invigorated this program by merging two pre-existing programs, re-evaluating the membership, identifying the leadership for focus groups, and recruiting new faculty to Duke and the DCI.
Aim #1: Foster interactions and collaborations around cancer genetics and genomics in the DCI.
To this aim we have developed program-wide and focus group activities. The program-wide activities include a monthly lunch talk series, the CGG yearly minisymposium, and the CGG annual grand rounds speaker. These are all well-attended and bring together a diverse group of investigators around the central themes of cancer genetics and genomics.
CGG is further organized into three focus groups: (a) The Focus Group on Epigenetics and Epigenomics. (b) The Focus Group on DNA Replication, Recombination and Repair. (c) The Focus Group on Gene Expression. The different focus groups organize distinct monthly research-in-progress sessions; all CGG members are welcomed to attend and indeed all DCI members can attend any of these meetings. The focus group activities provide additional opportunities for training, mentorship and interaction around more focused themes.
Aim #2: Promote sharing of expertise in computational and functional genomics in the DCI.
The advent of high throughput sequencing provides a powerful set of technologies that allow the high resolution definition of molecular aberrations of tumors. Through targeted investment in high throughput genomics, the DCI has enabled collaborations around high throughput sequencing. This investment has allowed the critical program growth in genomics, along with the development of an integrated data repository aggregation of all data, as well as streamlined use of the core facilities. This investment has in turn enabled a number of inter-program and inter-institutional collaborations within the DCI and beyond.
RNA interference screening provides a powerful approach to functionally dissect biological processes and cancer-related phenotypes. The RNAi Screening Facility of the Center for RNA Biology provides DCI investigators the expertise and infrastructure needed to conduct RNA interference screening for the high throughput identification of genes important in cancer. These screens have already resulted in high impact findings in other systems and are now being adapted to cancer, especially in combination with genetic studies that utilize next generation sequencing. In addition, the CGG program provides expertise in assays around genetic engineering methods such TALENs and CRISPR that provide powerful new methods for manipulating the genome.
The program serves to coordinate DCI research activities related to:
1. Cancer genetics
3. Gene expression (transcriptional and post - transcriptional)
4. Application of genomics technologies to assay alterations in cancer genomes, epigenomes and transcriptomes.
1.Epigenetics and Epigenomics
2.DNA Replication, Recombination and Repair
CGG is led by Drs. Sandeep Dave and Mariano A. Garcia-Blanco (Co-Directors). Dr. Dave is a physician-scientist and clinical oncologist. He is an Associate Professor of Medicine at Duke Institute for Genome Sciences and Policy at Duke University. He completed medical school, graduate school and business school at Northwestern University, and a clinical and post-doctoral fellowship at the National Institutes of Health. His work has focused on the application of genomics as a tool for unraveling the biology of lymphomas and for the identification of new diagnostic and prognostic markers in lymphomas (e.g. Dave et al, New England Journal of Medicine 2004 and Dave et al, NEJM 2006). He is the PI of several peer-reviewed grants including the NCI R01 (R01CA136895), a Research Scholar Grant from the American Cancer Society and a Translational Award from the V Foundation. Most recently, his lab has applied high throughput sequencing to unravel the genetic causes of lymphoma (e.g. Love et al, Nature Genetics 2012) and for understanding the genetic underpinnings of response to targeted therapies (e.g. Walsh et al, Clin Canc Research 2013). Within the DCI, Dr. Dave also leads the cancer genomics efforts that enable a number of inter-programmatic collaborations aimed at defining the molecular features of different cancers. Dr. Dave also leads the international Hematologic Malignancies Research Consortium, an international group of collaborating institutions that is focused on applying genomics to better define these cancers. The consortium includes several NCI-designated Comprehensive Cancer Centers. Dr. Dave organizes the monthly program-wide meetings along with Dr. Garcia-Blanco and hosts the external speakers for the monthly meeting and the yearly symposium.
Dr. Garcia-Blanco has made seminal and clinically relevant contributions to the fields of RNA biology and RNA virology. His studies on mRNA splicing have shed light on the mechanisms of splicing regulation, disease-causing mis-regulation of splicing and a new type of RNA therapy (Garcia-Blanco et al. 2004, Nature Biotechnology; Gregory et al (2007) Nature Genetics). Dr. Garcia-Blanco discovered the polypyrimidine tract binding protein, which was one of the first, if not the first, mammalian alternative splicing factor (Gil et al. 1991, Genes and Dev; Wagner and Garcia-Blanco 2002, Molecular Cell;). More recently he pioneered imaging of alternative splicing decisions in vivo and visualized splicing changes accompanying phenotypic transitions among metastatic cancer cells in living animals (Oltean et al. 2006, PNAS; Bonano et al. 2007, Nature Protocols; Oltean et al. 2008, Clin Exp Metastasis). This work led to the discovery of highly aggressive transitional cells among circulating tumor cells in patients with metastatic breast and prostate cancer (Armstrong et al. 2011, Mol Cancer Res). This is currently the basis for the discovery of new biomarkers in these patients, an ongoing collaboration with Dr. Andrew Armstrong of the Solid Tumor Therapeutics Program and the GU Cancer group. Dr. Garcia-Blanco has also made important contributions to our understanding of pathogenic flaviviruses, RNA viruses that infect hundreds of millions worldwide every year (Sessions et al. 2009, Nature; Ward et al., 2011, RNA Biology). In addition to his scholarly work Dr. Garcia-Blanco has provided service and leadership in the biomedical community both at Duke, in the US and internationally. He has been the Director of the Duke Center for RNA Biology since 2006. He served as permanent member and chair to the Biochemistry Study Section (NIH), and from 2008 -11 was a member of the National Advisory General Medical Sciences Council (NIGMS). Additionally, he served as a member of the scientific advisory board of the European Alternative Splicing Network (EURASNET), an EU grant, and was Chair of the scientific advisory board of a GenomeQuebec (Canada) Sherbrooke University multi-PI grant and helped these two group guide their programs for five years. He serves as member of the Scientific Advisory Board, NIGMS HIV/AIDS Structure Program. Dr. Garcia-Blanco was elected a member of the Association of American Physicians, and fellow of the American Association for the Advancement of Science and the American Academy of Microbiology. Dr. Garcia-Blanco directs the RNA related components of the Gene Expression focus group and organizes these monthly meetings. Furthermore as director of the Center for RNA Biology, Dr. Garcia-Blanco founded the Duke RNAi Screening Facility and oversees its operations. More recently he recruited Dr. So Young Kim to direct the Facility and to enhance its cancer focus. Dr. Garcia-Blanco is a member of the training faculty for the NCI T32 training grant in Cancer Biology, and member of the executive committee and training faculty member of the NCI T32 training grant in Viral Oncology.
Sequencing of Burkitt Lymphoma and the discovery of a novel tumor suppressor gene ID3. Love et al, Rizzieri, Dave (2012) Nature Genetics and Zhang et al Dave (2013) PNAS.
Structures of Human Exonuclease 1 DNA Complexes - critical insights into mismatch repair and genome stability. Orans et al Modrich and Beese (2011) Cell.
Mutagenic processing of ribonucleotides in DNA by topoisomerase I. Kim et al Jinks-Robertson (2011) Science.
ATM/Chk2-Mediated DNA Damage-Responsive Signaling Pathway Suppresses Epstein-Barr Virus Transformation. Nikitin et al, Dave, Luftig (2010) Cell Host and Microbe.
Epithelial plasticity among circulating tumor cells in patients with metastatic disease. Armstrong et al Garcia-Blanco (2011) Mol. Cancer Research [Reproduced in R A Weinberg The Biology of Cancer 2nd Edition; Patent application pending; Multiple clinical studies; Research Agreement with Johnson and Johnson (Janssen)]