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

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 AL, Peto J, Silva IDS, Couch FJ, Olson JE, Hillemans P, Park-Simon TW, 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 P, Beckmann M, Andrulis IL, Knight JA, Anton-Culver H, Ziogas A, Giles GG, Milne RL, Brenner H, Arndt V, Mannermaa A, Kosma VM, 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 (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 19

Pages Range: 599-603

Journal Issue: 5

DOI: 10.1038/gim.2016.147

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.

Authors with CRIS profile

Involved external institutions

London School of Hygiene and Tropical Medicine United Kingdom (GB) Mayo Clinic United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Oslo Norway (NO) Ruprecht-Karls-Universität Heidelberg Germany (DE) Technische Universität München (TUM) Germany (DE) Universität zu Köln Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Sheffield United Kingdom (GB) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Cancer Prevention Institute of California (CPIC) United States (USA) (US) Karolinska Institute Sweden (SE) University of Cambridge United Kingdom (GB) Stanford University United States (USA) (US) University of Copenhagen Denmark (DK) Erasmus University Medical Center (MC) Netherlands (NL) Helsingin yliopisto / University of Helsinki Finland (FI) National Cancer Institute (NCI) United States (USA) (US) Antoni van Leeuwenhoek Netherlands (NL) Bashkir State University / Башкирский государственный университет Russian Federation (RU) The Institute of Cancer Research (ICR) United Kingdom (GB) Leiden University Netherlands (NL) University of Toronto Canada (CA) University of Oxford United Kingdom (GB) The University of Melbourne Australia (AU) University of Eastern Finland Finland (FI) University of California Irvine United States (USA) (US) King’s College London United Kingdom (GB) Finnish Institute of Occupational Health (FIOH) / Työterveyslaitos (TTL) Finland (FI)

How to cite

APA:

Muranen, T.A., Greco, D., Blomqvist, C., Aittomaki, K., Khan, S., Hogervorst, F.,... Nevanlinna, H. (2017). Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics in Medicine, 19(5), 599-603. https://dx.doi.org/10.1038/gim.2016.147

MLA:

Muranen, Taru A., et al. "Genetic modifiers of CHEK2*1100delC-associated breast cancer risk." Genetics in Medicine 19.5 (2017): 599-603.

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