Cancer Genetics Program
Terry Magnuson, PhD and Jonathan Berg, MD, PhD
The “Genetic Revolution” has been in full force for two decades. Unprecedented biological insights have been gained, disease mechanisms have been glimpsed, and the entire human genome has been sequenced. Progress has been bolstered by the development of high-throughput capabilities to comprehensively sequence, profile, and analyze large numbers of tumors across tens of thousands of variables. Integrating basic research with clinical care to enable earlier detection and more curable forms of cancer and to develop more effective, highly targeted therapies is the beginning. The goal of the Cancer Genetics program is to catalyze breakthroughs in understanding mechanisms leading to cancer, along with diagnosis and therapy, by integrating strengths at UNC in genetic and molecular analysis from basic science through clinical application, and enabling integrated, high-throughput analyses. This vision is being realized through strategic recruitment of faculty in emerging fields, investment in cutting-edge technology and enhanced organizational capability for integrative analysis. This unified and integrated effort ensures that insights gained through basic research will not linger in the mouse lab but will lead directly to the analysis of corresponding areas in the human genome, which are critical in the genesis, progression, and treatment of cancer. The Cancer Genetics Program within UNC Lineberger was established in 2001 to host this multidisciplinary approach to research and clinical care. It is comprised of laboratory-based investigators, statistical geneticists, clinicians and clinical researchers focused on the genetic etiology of cancer. Current research efforts at UNC utilize a breadth of experimental organisms from yeast, worm, and mouse to human population and cell-based systems. The goal is to identify mechanisms that generate genomic changes and to define the specific lesions responsible for cancer phenotypes. Studies of known – and yet to be discovered – genes are providing important insights into the diversity of human tumors and are uncovering novel strategies for cancer therapy. The conceptual framework for the Cancer Genetics Program is that cancers progress via an evolutionary process involving accumulation of multiple abnormalities. These include single genes, gene combinations and epigenetic factors that contribute to cancer and influence penetrance. Individuals differ in their susceptibility to cancer based upon common, polymorphic differences in low penetrance cancer genes (modifiers) together with inheritance of high penetrance germline and somatic mutant genes in defined molecular pathways (e.g. BRCA1, p53, p16). Based on this framework, the Program Faculty have outlined five strategic areas for research emphasis:
1. Genome-wide strategies that depend on statistical tools to gather genome information. This approach requires the use of bioinformatics, databases, expression arrays and analysis of transcriptional networks to identify modifier genes and gene networks (systems genetics). These approaches go beyond the standard genotype-phenotype correlation toward understanding cross talk between genes and non-genetic influences on genes. This goal interfaces with the population-based studies of gene-environment interaction, nutritional factors, and cancer in minority populations of the Cancer Epidemiology Program.
2. High penetrance cancer genes in model systems, centering on the investigation of molecular pathways implicated in cancer development and their associated cause and effect relationships.
3. Loss of genome integrity in human cancers leading to uncontrolled cell growth, invasion and metastasis. The goals are to identify mechanisms that generate genomic changes and to define the specific lesions responsible for cancer phenotypes.
4. Epigenetic processes defined by the organization of the eukaryotic genome within chromatin and the involvement of this organization in regulation of DNA metabolism (transcription, replication, repair and recombination).
5. A state-of-the-art infrastructure that includes the field’s most advanced technology along with hiring a corps of highly skilled non-faculty computational scientists with a distinct career path at UNC devoted to program development and management. This team is working to push technology and its applications in new directions.