Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Purpose CHEK2*1100delC is a founder variant in European populations conferring a 2-3 fold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods With genotype data of 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results The PRS conferred an odds ratio (OR) of 1.59 [95% CI 1.21-2.09] per standard deviation for BC for CHEK2*1100delC carriers and 1.58 [1.55-1.62] for non-carriers. No evidence for deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 [0.86-4.78] and for the lowest quintile 0.52 [0.16-1.74] for CHEK2*1100delC carriers, corresponding to over 34.0% and less than 15.0% life-time risk, respectively. Conclusion Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify the carriers at a high life-time risk for clinical actions.