Kenneth Offit, MD, MPH

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, Drs. Offit and Robson have used a genomic scan to find genetic "protective factors." They published their discovery of one marker, near the gene ZNF365 on chromosome 10, which decreases risk of breast cancer about 25% in BRCA2 mutation carriers. This year, they have completed an analysis of 15,000 additional genetic markers in their sample set 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. Over the next year, this team will look for rare genetic variants that modify BRCA2 breast and ovarian cancer risk. They are also preparing to implement, in a research context, the first important steps toward actually bringing this additional testing to the clinic to inform the decisions of women at hereditary risk for breast cancer by virtue of an inherited BRCA mutation.

Mid-year Progress: The research team led by Drs. Offit and Robson continue to collect and send samples for analysis of rare genetic variants that modify BRCA2 breast and ovarian cancer risk. They will also be carrying out a second scan for common variants. They have successfully recruited a behavioral scientist who will arrive this spring to implement, in a research context, the first important steps toward actually bringing this additional testing to the clinic to inform the decisions of women at hereditary risk for breast cancer by virtue of an inherited BRCA mutation.

2) In a separate group of studies entitled "Genomic Susceptibility to Breast and Ovarian Cancer," Dr. Offott brings together several projects being developed in the current continuation. These proposals all use new "high throughput" next generation sequencing (NGS). Notable progress during the past year included the first identification in humans of a "spontaneous" change (not present in parents) in inherited DNA associated with cancer in an offspring compared to parental DNA. This was not observed in breast or colon cancer cases but in early onset male testicular cancer.

Dr. Offit's team is now analyzing the breast cancer "trios" for DNA mutations seen in offspring but not parents. During the past year, they identified several new variants in BRCA negative breast cancer, including mutations in the genes SLX4 and HOXB13. They initiated deep sequencing of BRCA negative breast and breast ovarian families, and found a novel mutation in one woman with both breast and ovarian cancer, and another shared mutation in several other individuals that they are further investigating.

During the upcoming period, Dr. Offit will continue with this sequencing effort, and introduce a new approach to "filter" variants by also sequencing the tumors. Finally, he and his team have written and taken through the MSKCC 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. This will mark a major challenge in the era of personalized genomic medicine.

Mid-year Progress: This project is studying "spontaneous" changes (not present in parents) in inherited DNA associated with cancer in an offspring compared to parental DNA ("trios"). Dr. Offit's group has published their first report of this analysis in collaboration with BCRF investigator Mike Wigler, PhD (Cold Spring Harbor Laboratory) and is now looking at these cancer "trios" for DNA mutations seen in offspring and not parents. As noted during the past year, this group identified several new variants in BRCA negative breast cancer, including mutations in the genes SLX4 and HOXB13. They initiated deep sequencing of BRCA negative breast and breast- ovarian families, and have found a large PALB2 deletion in one woman with both breast and ovarian cancer, and another shared mutation that we are further investigating. They are continuing with this sequencing effort, and combining data with other BCRF grantees at the Mayo Clinic and the University of Pennsylvania.

Finally, Dr. Offit's team is at the earliest steps of implementation of a study offering selected individuals the results of their full genome analysis, i.e. all of their known inherited risk to all diseases, which has raised operational, medical, as well as ethical challenges relating to personalized medicine. The group has submitted manuscripts on these issues.

Bio:
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 and was recently awarded an American Cancer Society Career Research Recognition Award. Dr Offit was a member of the Cancer Genetics Working Group of the National Cancer Institute and is Past Chair of the Cancer Genetics Subcommittee of the American Society of Clinical Oncology.

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 an early prospective study documenting a decreased risk of breast and ovarian caner following oophorectomy in women carrying inherited mutations of the BRCA genes. Dr Offit's group has led or contributed to the description and characterization of mutations associated with breast, ovarian, colon cancer, non-Hodgkin's lymphoma, and other malignancies. His laboratory currently focuses on the description of novel genetic mechanisms associated with increased risk for common malignancies, or which modify the risks of known hereditary predispositions.