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

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  • 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 Swerdlow
  • Montserrat García-Closas
  • Jonine Figueroa
  • Thilo Dörk
  • Natalia V Bogdanova
  • Per Hall
  • Jingmei 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 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
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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 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.147.

Original languageEnglish
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Volume19
Issue number5
Pages (from-to)599-603
DOIs
Publication statusPublished - May 2017

ID: 49378537