Breast Cancer Risk Gene Discovery: Opportunities and Challenges

Abstract

DNA-based testing has become routine in modern health care. Today, genetic testing for BRCA1 or BRCA2 germline mutations is routinely offered to women with personal and/or family history of breast cancer (BC) and/or ovarian cancer (OC). The identification of a pathogenic mutation in an index case allows relatives to be offered predictive testing and to provide clinical advice-related risk management to women with a high risk of BC and OC. A pathogenic BRCA1 or BRCA2 mutation is identified in less than 20 % of index cases tested, while variants of unknown biological and clinical significance (VUS) are detected in at least another 10 %. Additional BC predisposition genes (PALB2, RAD51C, RAD51D, XRCC2, RINT1, etc.) have been recently identified, and as a consequence of the introduction of new sequencing technologies into clinical testing laboratories, some of these genes are already being screened as part of gene panel testing. However, the use of these new BC-predisposing genes remains limited in clinical practice because their associated cancer risks are not precisely estimated at the present time due to the small number of families that are known to carry variants in these genes. Many more BC and OC genes with an expected wide range of associated risks remain unidentified. In this review, we will focus on recent advances in the field of BC genetics and will discuss future challenges for clinical utility of new tests.