Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Pilar Zamora M, Menendez-Rodriguez P, Hardisson D, Mendiola M, Gonzalez-Neira A, Pita G, Rosario Alonso M, Dennis J, Wang Q, Bolla MK, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Ko YD, Brauch H, Hamann U, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Matsuo K, Ito H, Iwata H, Tajima K, Li J, Brand JS, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lambrechts D, Peuteman G, Christiaens MR, Smeets A, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hartman M, Hui M, Lim WY, Chan CW, Marme F, Yang R, Bugert P, Lindblom A, Margolin S, Garcia-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Bojesen SE, Nordestgaard BG, Flyger H, Hooning MJ, Kriege M, Van Den Ouweland AMW, Koppert LB, Fletcher O, Johnson N, Dos-Santos-Silva I, Peto J, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Cox A, Cross SS, Reed MWR, Schmidt MK, Broeks A, Cornelissen S, Braaf L, Kang D, Choi JY, Park SK, Noh DY, Simard J, Dumont M, Goldberg MS, Labreche F, Fasching P, Hein A, Ekici AB, Beckmann M, Radice P, Peterlongo P, Azzollini J, Barile M, Sawyer E, Tomlinson I, Kerin M, Miller N, Hopper JL, Schmidt DF, Makalic E, Southey MC, Teo SH, Yip CH, Sivanandan K, Tay WT, Shen CY, Hsiung CN, Yu JC, Hou MF, Guenel P, Therese Truong , Sanchez M, Mulot C, Blot W, Cai Q, Nevanlinna H, Muranen TA, Aittomaki K, Blomqvist C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Bogdanova N, Doerk T, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Shu XO, Lu W, Gao YT, Zhang B, Couch FJ, Toland AE, Yannoukakos D, Sangrajrang S, Mckay J, Wang X, Olson JE, Vachon C, Purrington K, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Devilee P, Tollenaar RAEM, Seynaeve C, Czene K, Eriksson M, Humphreys K, Darabi H, Ahmed S, Shah M, Pharoah PDP, Hall P, Giles GG, Benitez J, Dunning AM, Chenevix-Trench G, Easton DF (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 23

Pages Range: 6096-111

Journal Issue: 22

DOI: 10.1093/hmg/ddu311

Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Authors with CRIS profile

Involved external institutions

Cancer Council Victoria Australia (AU) Ruprecht-Karls-Universität Heidelberg Germany (DE) University of Cambridge United Kingdom (GB) Hospital Monte Naranco Spain (ES) Hospital Universitario La Paz Spain (ES) Universidad Autónoma de Madrid (UAM) Spain (ES) University of Sheffield United Kingdom (GB) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University College London (UCL) United Kingdom (GB) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Robert-Bosch-Krankenhaus Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Mount Sinai Hospital (MSH) Canada (CA) University of Toronto Canada (CA) Kyushu University / 九州大学 Japan (JP) Aichi Cancer Center Research Institute Japan (JP) Mie University / 三重大学 Japan (JP) Genome Institute of Singapore Singapore (SG) Karolinska Institute Sweden (SE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Krebsregister Saarland / Saarland Cancer Registry Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) National University of Singapore (NUS) Singapore (SG) National University Health System (NUHS) Singapore (SG) National Cancer Institute (NCI) United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Herlev Hospital Denmark (DK) Copenhagen University Hospital Denmark (DK) Erasmus University Medical Center (MC) Netherlands (NL) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) London School of Hygiene and Tropical Medicine United Kingdom (GB) Vanderbilt University United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Oulun Yliopisto / University of Oulo Finland (FI) Evangelische Kliniken Bonn gGmbH Germany (DE) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Centre hospitalier universitaire de Québec Canada (CA) McGill University Canada (CA) Université de Montréal Canada (CA) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) IFOM - FIRC Institute of Molecular Oncology Italy (IT) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) King’s College London United Kingdom (GB) University of Oxford United Kingdom (GB) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) The University of Melbourne Australia (AU) Ramsay Sime Darby Health Care (RSDHC) Malaysia (MY) University of Malaya (UM) / Universiti Malaya Malaysia (MY) Academia Sinica / 中央研究院 Taiwan (TW) Tri-Service General Hospital (TSGH) / 三軍總醫院 Taiwan (TW) Kaohsiung Medical University (KMU) / 高雄醫學大學 Taiwan (TW) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Helsingin yliopisto / University of Helsinki Finland (FI) University of Southern California (USC) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Manchester United Kingdom (GB) University of Warwick United Kingdom (GB) Ministry of Public Health (MOPH) / กระทรวงสาธารณสุข Thailand (TH) University of Eastern Finland Finland (FI) Shanghai Center For Disease Control And Prevention (SCDC) China (CN) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) Mayo Clinic United States (USA) (US) Ohio State University United States (USA) (US) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) National Cancer Institute of Thailand Thailand (TH) International Agency for Research on Cancer (IARC) France (FR) University of Hawaii (U.H.) United States (USA) (US) Leiden University Netherlands (NL) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU)

How to cite

APA:

Milne, R.L., Burwinkel, B., Michailidou, K., Arias-Perez, J.-I., Pilar Zamora, M., Menendez-Rodriguez, P.,... Easton, D.F. (2014). Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium. Human Molecular Genetics, 23(22), 6096-111. https://doi.org/10.1093/hmg/ddu311

MLA:

Milne, Roger L., et al. "Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium." Human Molecular Genetics 23.22 (2014): 6096-111.

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