Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers

BACKGROUND: It is often assumed any cancer in a germline BRCA1 or BRCA2 (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals. METHODS: We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided. RESULTS: Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls (P = 1.0x10(−10) and P = 1.4x10(−34), respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations (P = 5.1x10(−10) and P = 3.7x10(−9)) and cancers without BRCA mutations (P = 2.8x10(−53) and P = 1.0x10(−134)). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS (P = 3.8x10(−17) and P = 1.6x10(−8)) or benign variants (P = 1.2x10(−28) and P = 2.2x10(−10)). There was no difference between individuals with BRCA VUS and those with benign variants. CONCLUSIONS: These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.