Modifiers of Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis

Inherited mutations in BRCA1and BRCA2 (BRCA1/2) are associated with an increased risk of developing breast and ovarian cancer (1,2). However, there is substantial interindividual variability in both the age at diagnosis and site of cancer occurrence in BRCA1/2 mutation carriers. A number of lines of evidence suggest that additional modifying factors influence cancer penetrance among BRCA1/2 mutation carriers. Cancer occurrences vary even among members of the same family who carry the same BRCA1/2 mutation (3). Begg et al. (4) reported that biases may exist in penetrance estimates (eg, lifetime cancer risk) if relevant covariables are ignored in estimating penetrance and concluded that modifiers are likely to exist that affect BRCA1/2-associated cancer penetrance. These observations suggest that modifiers of cancer risk may exist that could improve risk assessment in this high-risk population. Specific factors have been reported to be associated with modified cancer risk. Genetic variation at other loci affects breast or ovarian cancer penetrance in women who carry an inherited BRCA1/2 mutation (5–15). Studies of many of these factors have been undertaken using large samples and validated using state-of-the-art genome-wide association approaches. These loci are very likely to be valid modifiers of cancer risk in BRCA1/2 mutation carriers. A variety of exposures and lifestyle factors have been proposed to modify breast and ovarian cancer risk in BRCA1/2 mutation carriers (16). These modifiers of cancer risk include reproductive history and exposures such as smoking, alcohol consumption, or exogenous hormones. However, many of the studies published to date involve small sample sizes, “convenience” samples of BRCA1/2 mutation carriers, retrospective evaluation of risk factors, and other study design limitations. Many of these reports have not been validated using epidemiologically appropriate independent study samples. Thus, it remains unclear which (if any) of the putative modifiers of risk may truly influence a woman’s breast or ovarian cancer risk if she has inherited a BRCA1/2 mutation. Given the importance of accurate risk assessment information in this high-risk population, it is critical to understand the role that risk modifiers may contribute to the risk assessment process. Therefore, we undertook a systematic review of the literature regarding cancer risk modifiers in BRCA1/2 mutation carriers and have performed a meta-analysis of relevant data. Our results should inform the use of risk modifiers in cancer risk counseling, as well as highlight areas of research that are needed to resolve questions about modifiers that have been inadequately studied to date.