Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
; Greco, D; Blomqvist, C; Aittomäki, K; Khan, S; Hogervorst, F; Verhoef, S; Pharoah, PD; Dunning, AM; Shah, M; +66 more...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; NBCS Investigators; Peto, J; Dos Santos Silva, I; Couch, FJ; Olson, JE; Hillemans, P; Park-Simon, T; 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, JW; Fasching, PA; Beckmann, MW; Andrulis, IL; Knight, JA; kConFab/AOCS Investigators; Anton-Culver, H; Ziogas, A; Giles, GG; Milne, RL; Brenner, H; Arndt, V; Mannermaa, A; Kosma, V; 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 and
(2016)
Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
Genetics in medicine, 19 (5).
pp. 599-603.
ISSN 1098-3600
DOI: 10.1038/gim.2016.147
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.
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