Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold 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:Using genotype data from 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 odds ratios (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 noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.

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Keywords 1100delC, breast cancer, Breast Cancer Association Consortium, CHEK2, common variants, polygenic risk score
Persistent URL dx.doi.org/10.1038/gim.2016.147, hdl.handle.net/1765/108537
Journal Genetics in Medicine
Muranen, T.A. (Taru A.), Greco, D. (Dario), Blomqvist, C, Aittomäki, K, Khan, S, Hogervorst, F. (Frans), … Nevanlinna, H. (2017). Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk. Genetics in Medicine, 19(5), 599–603. doi:10.1038/gim.2016.147