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

  • Author(s): Muranen, Taru A;
  • Greco, Dario;
  • Blomqvist, Carl;
  • Aittomäki, Kristiina;
  • Khan, Sofia;
  • Hogervorst, Frans;
  • Verhoef, Senno;
  • Pharoah, Paul DP;
  • Dunning, Alison M;
  • Shah, Mitul;
  • Luben, Robert;
  • Bojesen, Stig E;
  • Nordestgaard, Børge G;
  • Schoemaker, Minouk;
  • Swerdlow, Anthony;
  • García-Closas, Montserrat;
  • Figueroa, Jonine;
  • Dörk, Thilo;
  • Bogdanova, Natalia V;
  • Hall, Per;
  • Li, Jingmei;
  • Khusnutdinova, Elza;
  • Bermisheva, Marina;
  • Kristensen, Vessela;
  • Borresen-Dale, Anne-Lise;
  • NBCS Investigators;
  • Peto, Julian;
  • Dos Santos Silva, Isabel;
  • Couch, Fergus J;
  • Olson, Janet E;
  • Hillemans, Peter;
  • Park-Simon, Tjoung-Won;
  • Brauch, Hiltrud;
  • Hamann, Ute;
  • Burwinkel, Barbara;
  • Marme, Frederik;
  • Meindl, Alfons;
  • Schmutzler, Rita K;
  • Cox, Angela;
  • Cross, Simon S;
  • Sawyer, Elinor J;
  • Tomlinson, Ian;
  • Lambrechts, Diether;
  • Moisse, Matthieu;
  • Lindblom, Annika;
  • Margolin, Sara;
  • Hollestelle, Antoinette;
  • Martens, John WM;
  • Fasching, Peter A;
  • Beckmann, Matthias W;
  • Andrulis, Irene L;
  • Knight, Julia A;
  • kConFab/AOCS Investigators;
  • Anton-Culver, Hoda;
  • Ziogas, Argyrios;
  • Giles, Graham G;
  • Milne, Roger L;
  • Brenner, Hermann;
  • Arndt, Volker;
  • Mannermaa, Arto;
  • Kosma, Veli-Matti;
  • Chang-Claude, Jenny;
  • Rudolph, Anja;
  • Devilee, Peter;
  • Seynaeve, Caroline;
  • Hopper, John L;
  • Southey, Melissa C;
  • John, Esther M;
  • Whittemore, Alice S;
  • Bolla, Manjeet K;
  • Wang, Qin;
  • Michailidou, Kyriaki;
  • Dennis, Joe;
  • Easton, Douglas F;
  • Schmidt, Marjanka K;
  • Nevanlinna, Heli
  • et al.
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.

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