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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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