Multidisciplinary Etiologic Studies of Hereditary Breast, Ovarian Cancer

Overview

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.

Background & Purpose

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 Megan Frone.

Clinical Genetics Branch - Research Areas

Study Publications

• Rebbeck TR, et al. No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study. Breast Cancer Res Treat 2009.
• Greene MH, Mai PL. What have we learned from risk-reducing salpingo-oophorectomy? J Natl Cancer Inst 2009.
• Antoniou AC, et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008.
• Osorio A, et al. An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2008.
• Katki HA, Gail MH, Greene MH. Breast-cancer risk in BRCA-mutation-negative women from BRCA-mutation-positive families. Lancet Oncol 2007.
• Antoniou AC, et al. RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007.
• Pereira LH, Pineda MA, Rowe WH, Fonseca LR, Greene MH, Offit K, Ellis NA, Zhang J, Collins A, Struewing JP. The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies. BMC Genet 2007.
• Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE; CIMBA. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 2007.
• Couch FJ, et al. AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev 2007.
• Spurdle AB, et al. The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2006.
• Kazerouni N, Greene MH, Lacey JV Jr, Mink PJ, Schairer C. Family history of breast cancer as a risk factor for ovarian cancer in a prospective study. Cancer 2006.
• McInerney-Leo A, Hadley D, Kase RG, Giambarresi TR, Struewing JP, Biesecker BB. BRCA1/2 testing in hereditary breast and ovarian cancer families III: risk perception and screening. Am J Med Genet A. 2006.
• Wideroff L, Vadaparampil ST, Greene MH, Taplin S, Olson L, Freedman AN. Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians. J Med Genet 2005.
• McInerney-Leo A et al. BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships. Am J Med Genet A. 2005.
• Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 2005.
• Struewing JP, Hartge P, Wacholder S, Tucker MA, Greene MH. BRCA1 and sex ratio. Eur J Hum Genet 2004.
• Mateus Pereira LH, et al. CHEK2:1100delC and female breast cancer in the United States. Int J Cancer 2004.
• McInerney-Leo A, Biesecker BB, Hadley DW, Kase RG, Giambarresi TR, Johnson E, Lerman C, Struewing JP. BRCA1/2 testing in hereditary breast and ovarian cancer families: effectiveness of problem-solving training as a counseling intervention. Am J Med Genet A 2004.
• Rutter JL, Smith AM, Dávila MR, Sigurdson AJ, Giusti RM, Pineda MA, Doody MM, Tucker MA, Greene MH, Zhang J, Struewing JP. Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Hum Mutat 2003.
• Giusti RM, Rutter JL, Duray PH, Freedman LS, Konichezky M, Fisher-Fischbein J, Greene MH, Maslansky B, Fischbein A, Gruber SB, Rennert G, Ronchetti RD, Hewitt SM, Struewing JP, Iscovich J. A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 2003. Erratum in: J Med Genet. 2004.
• Kazerouni N, Schairer C, Friedman HB, Lacey JV Jr, Greene MH. Family history of breast cancer as a determinant of the risk of developing endometrial cancer: a nationwide cohort study.J Med Genet 2002 Nov;39(11):826-32.
• Biesecker BB, Ishibe N, Hadley DW, Giambarresi TR, Kase RG, Lerman C, Struewing JP. Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families. Am J Med Genet 2000.