Abstract

Women carrying a pathogenic mutation in the BRCA2 gene have an increased risk of breast cancer. However, risk varies considerably between affected families. Our aim was to understand why risk can differ and what the predictors are. Our approach focused on other genetic variants that modify breast cancer risk.

We tried to identify some of these by comparing a large number of genetic variants in 4,330 BRCA2 mutation carriers with breast cancer and in 3,881 without. We analysed whether carrying a certain allele of a genetic variant was associated with increased or decreased likelihood of developing cancer.

A variant on chromosome 6 was significantly associated with risk of cancer. Those who carried the minor allele of this variant had a 25% decreased risk of breast cancer.

Risk predictors can be used to derive refined risk estimates for individuals carrying a BRCA2 mutation. These estimates are crucial in clinical management which can include decisions regarding preventive treatments. Furthermore, identification of genetic risk modifiers could help us improve our understanding of the biology of breast cancer development in these women.