Kenneth Offit, MD, MPH

Drs. Offit and Robson have completed the major aims of this project, which led to the identification of a new locus associated with a low risk for breast cancer in individuals of Ashkenazi Jewish background who have tested negative for BRCA mutations. Through ongoing studies they have identified new regions of the gene (on chromosomes 5, 6 and 16) associated with an increase in breast cancer of approximately 1.2-1.4 fold. Over the past year they have replicated findings of the chromosome 6 risk marker in Caucasian Ashkenazi Jewish as well as non-Ashkenazi women, and have noted the risk is greater for estrogen receptor positive breast cancer. They have started to unravel the possible genes involved and the relationship to estrogen. In the coming year they will focus on new (de novo) copy number variations in breast cancer susceptibility by comparing the genomes of parents and their offspring affected by breast cancer. This will enhance understanding of the genetic basis of seemingly "sporadic" early-onset breast cancers. Finding new breast cancer susceptibility genes could have broad applications in terms of improved breast cancer risk assessment and breast cancer prevention. If shown to play a role in breast cancer, copy-number variations may represent a new paradigm in our understanding of not only breast cancer, but all of cancer genetics.

In a related continuing project they are studying the validity of genomic testing for breast cancer risk, which is being offered by some commercial companies, but whose readiness for routine use the researchers have questioned. They have studied over 1000 women in their clinic who have tested negative for BRCA mutations and who have consented to prospective research to quantify new markers of genetic risk. They have compared genomic risk to traditional risk models in these women. This study will continue to evaluate the best way to use genomic markers for individual risk assessment and set the stage for offering the results of genomic risk information to women in the setting of a behavioral study.

Dr. Offit is also leading a project, in collaboration with the Broad Institute, supported by BCRF. A decade 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 BRCA mutation will develop breast, ovarian, or other cancers at different ages or not at all (Offit, 2006). It is the hypothesis of this proposal that there exist genetic "protective factors" (alleles) which interact with known genetic risk markers, and which may serve as breast cancer or ovarian cancer protective factors in the general population. Over the past year, this project has succeeded in the assembly of DNA samples from over 6,000 women with BRCA2 mutations around the world. This collection of DNA samples has involved close coordination with colleagues at the Broad Institute at Harvard/MIT. Dr. Offit and team have completed half of the first phase of whole genome analysis, with genotyping to be finished by the end of the summer of 2009. They are coordinating our analysis with BCRF colleagues at the Mayo Clinic, who are looking at modifiers of BRCA1 mutations.

Mid-Year Progress Report:
In the Ashkenazi Jewish population, Drs. Offit and Robson have previously discovered a new breast cancer susceptibility marker, or genetic variant, on chromosome 6. In the past 6 months they replicated this finding in 1500 breast cancer cases and 1500 healthy women of various ancestries. In addition, using the large international resources of the Breast Cancer Association Consortium, of which their group is a member, they genetically analyzed over 50,000 breast cases and healthy individuals. These findings confirmed a significant, but weak effect for this genetic variant (called a "SNP") in terms of increased risk for breast cancer. Interestingly, this same variant affected risk in women carrying BRCA1 mutations.

In a separate but related study, the researchers have attempted to judge the clinical usefulness of this SNP, as well as a dozen others reported by other groups to have weak effects on breast cancer risk. They report, for the first time, that these SNPs can modestly improve to the ability to predict risk using accepted characteristics (such as age of menarche, number of children, and family history). Finally, in a new study looking at the genetic basis of seemingly non familial breast cancer, they have made good progress in collecting DNA samples from cancer cases as well as healthy parents. This DNA will be analyzed in collaboration with their BCRF colleague, Dr Michael Wigler.

It is the hypothesis of Dr. Offit's 5-year project in connection with the Broad Instiute that there exist genetic "protective factors" (alleles) which interact with known genetic risk markers, and which may serve as breast cancer or ovarian cancer protective factors in the general population. Over the past year, this project has completed assembly of DNA samples from over 6,000 women with BRCA2 mutations around the world. At the Broad institute of Harvard Dr. Offit and colleagues have carried out a genome scan of 2,000 DNA samples from older unaffected and younger women affected by breast cancer. The top 96 genetic markers differing in these groups ("protective factors") are being screened in an additional 3,000 cases. They are also coordinating their analysis with BCRF colleagues at the Mayo Clinic, who are looking at modifiers of BRCA1 mutations.

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.