BRCA1/2 Modifier Loci

Several lines of evidence suggest that there may be important genetic modifiers of the risk of cancer among women with germline mutations in the BRCA1 or BRCA2 genes. The first is the fact that, despite very high early estimates of penetrance, performed largely in the multiple-case families used in positional cloning efforts, studies in more population-based settings suggest that the risk of breast cancer is 50% or lower by age 70. Since we know that in some families the penetrance is nearly complete, if the average risk is indeed below 50%, then there is considerable variability in risk that may be mediated by modifying genetic loci. Another observation consistent with modifying factors (be they genetic or environmental) is the considerable heterogeneity observed in ovarian cancer risk even for families segregating the same BRCA1/2 mutation. While both of these observations could reflect random variability in cancer risk, I believe they are more suggestive of the presence of modifiers.

In addition to approximately 250 female mutation carriers from intramural studies in collaboration with Mark Greene in the Clinical Genetics Branch, we are performing BRCA1/BRCA2 mutation analysis in the large National Ovarian Cancer Prevention and Early Detection Study (GOG-199). This study aims to enroll approximately 800 mutation carriers. Targeted studies of candidate modifier alleles are being conducted within our population, and potential modifiers are further evaluated in the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA). This is a large collaborative group of over 20 centers from around the world studying over 10,000 female BRCA1/BRCA2 mutation carriers. In addition to candidate genes-alleles, we are collaborating with Ken Offit at Memorial Sloan-Kettering Cancer Center to conduct genome-wide single nucleotide SNP studies using the Affymetrix 500k platform. This study involves contrasting Ashkenazi BRCA2:6174delT carriers who developed breast cancer before age 45 with carriers who are over age 65 and free of breast cancer.