Kenneth Offit, MD, MPH
Vice Chairman, Academic Affairs, Department of Medicine
Vice Chairman, Program in Cancer Prevention Control and Population Research
Department of Clinical Genetics Service
Memorial Sloan-Kettering Cancer Center
Member, Cancer Biology and Genetics Program (joint), Sloan-Kettering Institute
Professor of Medicine and Public Health, Weill Cornell Medical College
New York, New York
2013-2014 BCRF Projects:
1) The Sandra Taub Memorial Award
Co-Investigator: Mark E. Robson, MD, Memorial Sloan-Kettering Cancer Center, New York
A decade and a half after the initial identification of BRCA1 and BRCA2, there remains considerable uncertainty regarding cancer risks associated with inherited mutations of these genes. The basis of this variation of risk is most striking for BRCA2 and affects clinical management: patients with the same BRCA2 mutation will develop breast, ovarian, or other cancers at different ages or not at all. In this international study, we used a genomic scan to find genetic “protective factors.” We published our discovery of one marker, near the gene ZNF365 on chromosome 10, which decreases risk of breast cancer about 25% in BRCA2 mutation carriers. In this past year, Drs. Offit and Robson published in PLoS Genetics their analysis of ~10,000 BRCA2 carriers worldwide and identified the first genetic marker found to modify risk of breast cancer only in BRCA2 mutation carriers. This marker on chromosome 6 near the gene TFAP2A was associated with a 15% reduction in breast cancer risk in BRCA2 mutation carriers. Drs. Offit, Robson, and others also completed preliminary analysis using the “exome chip” and contributed a list of candidates to the “Oncochip” that will be used to test >600,000 cancer samples next year. Looking forward, they have recruited a behavioral scientist and have already begun work on a clinical research protocol to bring this testing for “genomic modifiers” to the clinic to inform the decisions of women at hereditary risk for breast cancer by virtue of an inherited BRCA2 mutation.
Dr. Offit is partnering with Dr. Mark Robson to identify markers influencing risk for those carrying BRCA2 mutations. Two decades after the initial identification of BRCA1 and BRCA2 there remains considerable uncertainty regarding cancer risks associated with inherited mutations of these genes. The basis of this variation of risk is most striking for BRCA2, and affects clinical management: patients with the same BRCA2 mutation will develop breast, ovarian, or other cancers at different ages or not at all. In this international study, the Offit-Robson team has used genomic scans to identify genetic “protective factors” near the gene ZNF365 on chromosome 10, as well as a marker on chromosome 6 near the gene TFAP2Aa, the first genetic marker found to modify risk of breast cancer only in BRCA2 mutation carriers. They are currently in the process of assembling and analyzing samples from 10,000 BRCA2 mutation carriers as part of the “Oncochip” that will be used to test >600,000 cancer samples this year. The researchers have also assembled a team including a behavioral scientist who has begun developing a clinical research protocol to bring this testing for “genomic modifiers” to the clinic to inform the decisions of women at hereditary risk for breast cancer by virtue of an inherited BRCA2 mutation.
2) Dr. Offit is conducting a second project entitled “Genomic Susceptibility to Breast and Ovarian Cancer,” which brings together several studies using “next generation sequencing” (NGS) to define causes of inherited breast and ovarian cancer. In 2013-2014, his team will continue their ascertainment of parent child trios to identify de novo rare mutations associated with early onset breast cancer. The major focus of this grant period will be pursue the collaboration established with co-BCRF grantees Drs. Katherine Nathanson (University of Pennsylvania) and Fergus Couch (Mayo Clinic) in order to combine their variant data on BRCA negative breast cancer kindreds (joint) breast ovarian cancer probands (MSKCC) and early onset breast cancer cases (MSKCC-Broad). These investigators are also committed to translating genomic information to patients, both to guide breast cancer prevention as well as to inform other aspects of their health care (based in the “incidentalome”) as part of "personalized preventive medicine."
The project “Genomic Susceptibility to Breast and Ovarian Cancer,” brings together several studies using “next generation sequencing” (NGS) to define causes of inherited breast and ovarian cancer. Dr. Offit’s team reports the publication of a novel approach where they sequenced the genomes of both the breast and ovarian tumors as well as inherited DNA of a woman with BRCA negative breast and ovarian cancer to detect a large genomic deletion. They are continuing their effort to discover novel mutations in BRCA negative families affected by breast cancer. Via weekly conference calls and data exchange with BCRF grantees at the Mayo Clinic and the University of Pennsylvania, they have created a working consortium and have recently received a first percentile score in a joint NCI application with these colleagues aimed to discover new breast cancer predisposing genes. They are continuing analysis of their project studying “spontaneous” changes (not present in parents) in inherited DNA associated with cancer in a young patient with breast cancer compared to parental DNA (“trios”). Finally, they have taken through their institutional review board a protocol to allow them to offer to selected individuals the results of their full genome analysis, i.e. all of their known inherited risk to all diseases. They have now enrolled four individuals (of 50 planned) on this study which is a model for the future of personalized genomics. The researchers have published several papers over the past months bearing on the operational, medical, as well as ethical challenges of personalized genomic counseling.
Kenneth Offit is Chief of the Clinical Genetics Service in the Department of Medicine at Memorial Sloan-Kettering Cancer Center. He is also Professor of Medicine and Public Health at Weill Medical College of Cornell University, and Vice Chairman of the Program in Prevention, Control and Population Research at MSKCC. He received his AB at Princeton University and his MD and MPH from the Harvard Medical School and the Harvard School of Public Health. He is a member of the American Society for Clinical Investigation. He was awarded an American Cancer Society Career Research Recognition Award and the 2013 ASCO American Cancer Society Award for research in cancer prevention. Dr Offit is a member of the Board of Scientific Counselors of the National Cancer Institute, and of the Evaluation of Genomic Applications in Practice and Prevention working group of the U.S. Centers for Disease Control.
Dr Offit's research team identified the most common mutation associated with hereditary breast and ovarian cancer in those of Ashkenazi Jewish ancestry. His group also published the first prospective study documenting a decreased risk of breast and ovarian cancer following oophorectomy in women carrying inherited mutations of the BRCA genes, and the first genome wide association study of BRCA2 mutation carriers. Dr Offit's group has discovered or characterized inherited mutations associated with risk of breast, ovarian, colon cancer, non-Hodgkin's lymphoma, and other malignancies. His laboratory currently focuses on utilizing genomic approaches to discover novel mechanisms associated with increased risk for common malignancies, or which modify the risks of known hereditary predispositions.