Population-Wide Screening for Germline BRCA1 and BRCA2 Mutations: Too Much of a Good Thing?

Abstract

Germline testing for highly penetrant mutations in cancer susceptibility genes such as BRCA1 and BRCA2 (BRCA1/2) can prevent cancer and save lives. Inherited BRCA1/2 mutations confer a 39% to 85% lifetime risk of female breast cancer and an 11% to 62% lifetime risk of ovarian cancer. Identifying BRCA1/2 mutation carriers thus allows for prophylactic surgeries, which can markedly decrease cancer incidence, morbidity, and mortality. Despite these benefits and increasing public awareness, a low fraction (35% in a recent Israeli study) of women with high-risk histories have undergone BRCA1/2 testing. Moreover, women from families with few female relatives are unlikely to recognize their risk of carrying a BRCA1/2 mutation until they themselves develop cancer. Recently, citing the impact of riskreducing surgeries, King et al published a high-profile appeal for BRCA1/2 mutation screening to be offered to all US women at age 30 years. King is to be commended for stimulating a serious discussion on the potential impact of bringing modern genetic medicine to the general population in a compelling circumstance. However, because testing all women for BRCA1/2 mutations would represent the first population-based screening for a hereditary cancer syndrome, careful consideration of the potential limitations, risks, and benefits of population-wide BRCA1/2 testing is essential. Currently, genetic screening efforts in the general population examine newborns for rare recessive disorders (eg, phenylketonuria, beta thalassemia) or screen prenatally for carriers of populationdependent recessive conditions (eg, Tay-Sachs, cystic fibrosis), seeking to prevent morbidity and mortality from childhood-onset diseases. In the case of autosomal dominantly inherited BRCA1/2 mutations, the goal is to reduce suffering and mortality from associated adult-onset malignancies, particularly in individuals who would not otherwise be aware of their cancer risk. Demonstration studies in the Ashkenazi Jewish population have shown that screening for its three BRCA1/2 founder mutations (with a combined 1-in-40 prevalence among unselected Ashkenazi Jews) is cost-effective and identifies carriers who would not have been suspected on the basis of their family cancer history. Citing a recent study of population-wide screening for the Ashkenazi founder mutations in Israel, King et al claim that the high penetrance of BRCA1/2 mutations is independent of whether patients who carry the mutations are ascertained on the basis of family history. However, all such studies examined Ashkenazi founder mutations only, which constitute more than 90% of mutations in the Ashkenazi population, thereby limiting generalizability to other populations. In the general US population, in which combined prevalence of a diverse array of BRCA1/2 mutations is 10-fold lower, widespread screening would have different performance characteristics than in the Ashkenazim. Whether the assortment of BRCA1/2 mutations found in non-Ashkenazi populations would have the same penetrance in population-based ascertainment as they do in clinicbased patients is unknown.