1. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
- Author
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Muranen, TA, Greco, D, Blomqvist, C, Aittomaki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE, Nordestgaard, BG, Schoemaker, M, Swerdlow, A, Garcia-Closas, M, Figueroa, J, Doerk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Peto, J, Silva, IDS, 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, 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, Muranen, TA, Greco, D, Blomqvist, C, Aittomaki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE, Nordestgaard, BG, Schoemaker, M, Swerdlow, A, Garcia-Closas, M, Figueroa, J, Doerk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Peto, J, Silva, IDS, 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, 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, and Nevanlinna, H
- Abstract
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.
- Published
- 2017