Two decades after BRCA: setting paradigms in personalized cancer care and prevention

Abstract

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Fig. 1. Genetic variants that predispose to breast cancer

The pie chart on the left shows the estimated percentage contribution of mutations in highpenetrance (BRCA1/2, TP53, CDH1, LKB1, and PTEN) and moderate-penetrance (e.g., CHEK2, ATM, and PALB2) genes and common low-penetrance genetic variants to familial relative risk. Common genetic variants are denoted as SNPs. “Known SNPs” are SNPs associated with breast cancer through GWAS, as listed on the right. The odds ratios refer to the increase (or, in some cases, the reduction) in risk conferred by the rare allele of the variants. “Other predicted SNPs” refers to the estimated contribution of all SNPs, other than known loci, that were selected for replication of breast cancer GWAS (5, 39).