Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk

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

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27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)599-603
Number of pages5
JournalGenetics in Medicine
Volume19
Issue number5
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

Keywords

  • 1100delC
  • breast cancer
  • Breast Cancer Association Consortium
  • CHEK2
  • common variants
  • polygenic risk score

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