Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
Muranen TA., Greco D., Blomqvist C., Aittomäki K., Khan S., Hogervorst F., Verhoef S., Pharoah PDP., Dunning AM., Shah M., Luben R., Bojesen SE., Nordestgaard BG., Schoemaker M., Swerdlow A., García-Closas M., Figueroa J., Dörk T., Bogdanova NV., Hall P., Li J., Khusnutdinova E., Bermisheva M., Kristensen V., Borresen-Dale A-L., NBCS Investigators None., Peto J., Dos Santos Silva I., Couch FJ., Olson JE., Hillemans P., Park-Simon T-W., Brauch H., Hamann U., Burwinkel B., Marme F., Meindl A., Schmutzler RK., Cox A., Cross SS., Sawyer EJ., Tomlinson I., Lambrechts D., Moisse M., Lindblom A., Margolin S., Hollestelle A., Martens JWM., Fasching PA., Beckmann MW., Andrulis IL., Knight JA., kConFab/AOCS Investigators None., Anton-Culver H., Ziogas A., Giles GG., Milne RL., Brenner H., Arndt V., Mannermaa A., Kosma V-M., Chang-Claude J., Rudolph A., Devilee P., Seynaeve C., Hopper JL., Southey MC., John EM., Whittemore AS., Bolla MK., Wang Q., Michailidou K., Dennis J., Easton DF., Schmidt MK., Nevanlinna H.
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.Genet Med advance online publication 06 October 2016.