Multidisciplinary Etiologic Studies of Hereditary Breast,Ovarian Cancer
Closed to Patient Enrollment, Data Analysis Ongoing
DCEG has been studying the Hereditary Breast/Ovarian Cancer (HBOC) syndrome since the 1960s; it now comprises a genetic disease paradigm for addressing vital translational clinical cancer genetics research questions. Resources include a prospective cohort of 32 BRCA mutation-positive families with extensive clinical and epidemiologic information, as well as biological samples. One hundred fifty new mutation-positive families have enrolled during the past several years. This study is now closed to new patient enrollment. Patient- related clinical activities have ended. Our focus will be on analyzing previously-collected data.
The Clinical Genetics Branch (CGB) HBOC family cohort was part of the original international collaborative research effort coordinated by the Breast Cancer Linkage Consortium that contributed to the mapping and cloning of BRCA1 and BRCA2. More recent research highlights include documenting a 62% reduction in breast cancer risk among women undergoing risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA mutation-positive families, a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment, and definitive-negative candidate gene studies analyzing genetic modifiers of BRCA1/2-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1/2 ("CIMBA") project, and. The most noteworthy CIMBA-related findings include confirmation that RAD51 significantly modifies the risk of BRCA2-related breast cancer, and that FGFR2 and TNRC9 (modifiers of sporadic breast cancer risk that were identified through the analysis of unselected breast cancer cases) also play important roles in the risk of BRCA-related breast cancer.
We plan additional clinical, genetic, behavioral and translational research studies of the cohort of DCEG hereditary breast/ovarian cancer (HBOC) families. In those families in which we have documented disease-related mutations in BRCA1 and BRCA2, the initial effort will be focused on providing genetic risk assessment, pre-test counseling and clinical germline mutation testing for those members of the CGB cohort of HBOC families who have been long-term participants in DCEG studies over the past 30 years. The members of these families have been invited to participate in other CGB protocols, including the Breast Imaging/Breast Duct Lavage study, the National Ovarian Cancer Prevention and Early Detection study, and a Phase I PARP-inhibitor trial targeting women at increased genetic risk of ovarian cancer being run by investigators in NCI's Center for Cancer Research (CCR). We have also collaborated with CCR's breast cancer Phase II chemoprevention trials of raloxifene and exemestane, and its pilot study of increasing physical activity as a breast cancer risk-reduction strategy.
DNA collected from these families is being contributed to an international collaboration seeking genetic modifiers of BRCA1 and BRCA2 penetrance, using both the candidate gene and genome-wide association study (GWAS) research strategies. Our BRCA mutation-negative families are being used to evaluate new candidate breast/ovarian cancer susceptibility genes. These families are also eligible to participate in various ancillary studies evaluating behavioral and psychosocial aspects of being at increased genetic risk of breast and ovarian cancer. We are currently analyzing the prospective risk of breast cancer among BRCA mutation-negative members of mutation-positive families, after an average of 18 years of follow-up. This is one of the very few long-term prospective studies of cancer risk in families with known BRCA mutations.
For more information, contact Mark H. Greene.