GEMO, a National Resource to Study Genetic Modifiers of Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers

Women carrying a pathogenic variant (PV) in the BRCA1 or BRCA2 (BRCA1/2) genes are at high lifetime risk of developing breast cancer (BC) and ovarian cancer (OC), but estimation of the cumulative risk of cancer to age 70 years varies substantially between studies and populations. Initial estimations were obtained from selected high-risk families with multiple cases, such as those ascertained through the Breast Cancer Linkage Consortium used to identify disease loci (1). In the first retrospective studies conducted on such families, estimates for BC ranged from 40 to 87% for BRCA1 PV carriers and from 27 to 84% for BRCA2 PV carriers and estimates for OC ranged from 16 to 68% for BRCA1 PV carriers and from 11 to 27% for BRCA2 PV carriers (1–4). Recently, the largest prospective cohort conducted to date reported cumulative risks of BC to age 80 years of 72% for BRCA1 PV carriers and 69% for BRCA2 PV carriers (5). In the same study, cumulative risks of OC to age 80 years were 44% for BRCA1 PV carriers and 17% for BRCA2 PV carriers. Variation in cancer risks within or between BRCA1/2 families, with respect to age at diagnosis or type of cancer, can be explained by other genetic factors and/or lifestyle and reproductive factors (6–10). Genome-wide association studies (GWAS) conducted by the Breast Cancer Association Consortium (BCAC) have identified 172 common single-nucleotide polymorphisms (SNPs) associated with small increases in breast and/or ovarian cancer risk in the general population (11). A subset of these SNPs modifies the risk of breast and ovarian cancer risk for BRCA1/2 PV carriers (12–14) but most of the variability has not been explained yet (15). Breast and ovarian cancer risks in BRCA1/2 PV carriers might also vary according to the location of the variant and/or its origin (14, 16–19). Genetic testing for BRCA1 and BRCA2 has been part of genetic counseling in European Union countries and North America since their discovery in the 90's, and has greatly improved recommendations about clinical management options and the most appropriate treatments. Nonetheless, both retrospective and prospective studies on large datasets of BRCA1/2 PV carrier families are still very much needed to refine individual cancer risk estimates by considering other genetic and lifestyle/environmental factors, and they will also contribute to a better understanding of the correlation between mutant BRCA1/2 alleles and phenotype. In particular, accurate age-specific risk estimates for the different types of cancer would be useful when choosing risk reduction strategies such as prophylactic bilateral mastectomy or salphingo-oophorectomy. The Genetic Modifiers of BRCA1 and BRCA2 (GEMO) Group is the French multidisciplinary, collaborative framework for the investigation of genetic factors modifying cancer risk in Hereditary Breast and Ovarian cancer (HBOC) families segregating BRCA1/2 PVs. Its primary aims are to contribute to large-scale national and international projects to identify genetic modifiers and to facilitate the translation of research results to the clinical setting. This is achieved by establishing a resource of blood DNA samples from individuals carrying a PV together with family and clinical data through the nation-wide network of cancer genetic clinics. Here we report on the progress of the GEMO study, the characteristics of the 5,303 actual participants and the prevalence and spectrum of BRCA1/2 cancer-associated variants identified so far.