Hereditary ovarian cancer: beyond the usual suspects

Abstract

In the past, hereditary ovarian carcinoma was attributed almost entirely to mutations in BRCA1 and BRCA2, with a much smaller contribution from mutations in DNA mismatch repair genes. Recently, three new ovarian cancer susceptibility genes have been identified: RAD51C, RAD51D, and BRIP1. In addition, germline mutations in women with ovarian carcinoma have been recently identified in many of the previously identified breast cancer genes in the Fanconi anemia (FA)-BRCA pathway. While mutations in genes other than BRCA1 and BRCA2 are each individually rare, together they make up a significant proportion of cases. With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes. As the cost of genomic sequencing continues to fall, the practice of evaluating cancer susceptibility one gene at a time is rapidly becoming obsolete. New advances in genomic technologies will likely accelerate the discovery of additional cancer susceptibility genes and increase the feasibility of comprehensive evaluation of multiple genes simultaneously at low cost. Improved recognition of inherited risk will identify individuals who are candidates for targeted prevention. In addition, identifying inherited mutations in a variety of FA-BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors.