Women's cancers: how the discovery of BRCA genes is driving current concepts of cancer biology and therapeutics

Over the last two decades, discoveries related to the breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) have profoundly changed our understanding and management of hereditary breast and ovarian cancers. The concept of synthetic lethality, which arises when cells become vulnerable to a combination of deficiencies in DNA repair, has driven the expanding roles of poly (adenosine diphosphate (ADP)-ribose) polymerase inhibitors in breast and ovarian cancers, and prevention strategies are taking into account the tissue specificity, natural history (fallopian tube origin of some high-grade serous ovarian cancers) and hormone sensitivity of BRCA-associated cancers. Current research has focussed on further elucidating the roles of BRCA proteins in DNA repair, investigating other key DNA repair processes and proteins and linking aberrant DNA repair with carcinogenesis. The ultimate goal is to translate this evolving knowledge into improving the clinical care and treatment of patients with pathogenic BRCA variants or other deficiencies in homologous recombination (HR). In this review, we will discuss 1) the role of BRCA proteins in DNA repair; 2) emerging concepts in the biology of HR deficiency and 3) implications for prevention and treatment.