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

Milne RL 1 , Burwinkel B 2 , Michailidou K 3 , Arias-Perez JI 4 , Zamora MP 5 , Menéndez-Rodríguez P 4 Show all authors , Hardisson D 6 , Mendiola M 7 , González-Neira A 8 , Pita G 8 , Alonso MR 8 , Dennis J 3 , Wang Q 3 , Bolla MK 3 , Swerdlow A 9 , Ashworth A 10 , Orr N 10 , Schoemaker M 11 , Ko YD 12 , Brauch H 13 , Hamann U 14 , GENICA Network , Andrulis IL 15 , Knight JA 16 , Glendon G 17 , Tchatchou S 18 , kConFab Investigators , Australian Ovarian Cancer Study Group , Matsuo K 19 , Ito H 20 , Iwata H 21 , Tajima K 22 , Li J 23 , Brand JS 24 , Brenner H 25 , Dieffenbach AK 25 , Arndt V 26 , Stegmaier C 27 , Lambrechts D 28 , Peuteman G 28 , Christiaens MR 29 , Smeets A 29 , Jakubowska A 30 , Lubinski J 30 , Jaworska-Bieniek K 30 , Durda K 30 , Hartman M 31 , Hui M 32 , Yen Lim W 32 , Wan Chan C 33 , Marme F 34 , Yang R 34 , Bugert P 35 , Lindblom A 36 , Margolin S 37 , García-Closas M 38 , Chanock SJ 39 , Lissowska J 40 , Figueroa JD 39 , Bojesen SE 41 , Nordestgaard BG 41 , Flyger H 42 , Hooning MJ 43 , Kriege M 43 , van den Ouweland AM 44 , Koppert LB 45 , Fletcher O 46 , Johnson N 46 , dos-Santos-Silva I 47 , Peto J 47 , Zheng W 48 , Deming-Halverson S 48 , Shrubsole MJ 48 , Long J 48 , Chang-Claude J 49 , Rudolph A 49 , Seibold P 49 , Flesch-Janys D 50 , Winqvist R 51 , Pylkäs K 51 , Jukkola-Vuorinen A 52 , Grip M 53 , Cox A 54 , Cross SS 55 , Reed MW 54 , Schmidt MK 56 , Broeks A 56 , Cornelissen S 56 , Braaf L 56 , Kang D 57 , Choi JY 58 , Park SK 57 , Noh DY 59 , Simard J 60 , Dumont M 60 , Goldberg MS 61 , Labrèche F 62 , Fasching PA 63 , Hein A 64 , Ekici AB 65 , Beckmann MW 64 , Radice P 66 , Peterlongo P 67 , Azzollini J 68 , Barile M 69 , Sawyer E 70 , Tomlinson I 71 , Kerin M 72 , Miller N 72 , Hopper JL 73 , Schmidt DF 73 , Makalic E 73 , Southey MC 74 , Hwang Teo S 75 , Har Yip C 76 , Sivanandan K 77 , Tay WT 78 , Shen CY 79 , Hsiung CN 80 , Yu JC 81 , Hou MF 82 , Guénel P 83 , Truong T 83 , Sanchez M 83 , Mulot C 84 , Blot W 85 , Cai Q 85 , Nevanlinna H 86 , Muranen TA 86 , Aittomäki K 87 , Blomqvist C 88 , Wu AH 89 , Tseng CC 89 , Van Den Berg D 89 , Stram DO 89 , Bogdanova N 90 , Dörk T 91 , Muir K 92 , Lophatananon A 93 , Stewart-Brown S 93 , Siriwanarangsan P 94 , Mannermaa A 95 , Kataja V 96 , Kosma VM 95 , Hartikainen JM 95 , Shu XO 48 , Lu W 97 , Gao YT 98 , Zhang B 48 , Couch FJ 99 , Toland AE 100 , TNBCC , Yannoukakos D 101 , Sangrajrang S 102 , McKay J 103 , Wang X 104 , Olson JE 105 , Vachon C 105 , Purrington K 105 , Severi G 106 , Baglietto L 106 , Haiman CA 89 , Henderson BE 89 , Schumacher F 89 , Le Marchand L 107 , Devilee P 108 , Tollenaar RA 109 , Seynaeve C 43 , Czene K 24 , Eriksson M 24 , Humphreys K 24 , Darabi H 24 , Ahmed S 110 , Shah M 110 , Pharoah PD 111 , Hall P 24 , Giles GG 106 , Benítez J 112 , Dunning AM 110 , Chenevix-Trench G 113 , Easton DF 111

Affiliations 

  • 1 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Human Cancer Genetics Programme, roger.milne@cancervic.org.au
  • 2 Department of Obstetrics and Gynecology, Molecular Epidemiology Group
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care
  • 4 Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain
  • 5 Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain
  • 6 Department of Pathology, Hospital Universitario La Paz, IdiPAZ (Hospital La Paz Institute for Health Research) Universidad Autonoma de Madrid, Madrid, Spain
  • 7 Laboratory of Pathology and Oncology, Research Unit, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
  • 8 Human Genotyping-CEGEN Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • 9 Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK, Division of Breast Cancer Research
  • 10 Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research
  • 11 Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK
  • 12 Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
  • 13 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany
  • 14 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
  • 15 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, Department of Molecular Genetics
  • 16 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
  • 17 Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
  • 18 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  • 19 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
  • 20 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 21 Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
  • 22 Department of Public Health & Occupational Medicine, Mie University Graduate School of Medicine, Tsu, Japan
  • 23 Human Genetics Division, Genome Institute of Singapore, Singapore
  • 24 Department of Medical Epidemiology and Biostatistics
  • 25 Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany
  • 26 Division of Clinical Epidemiology and Aging Research
  • 27 Saarland Cancer Registry, Saarbrücken, Germany
  • 28 Vesalius Research Center (VRC), VIB, Leuven, Belgium
  • 29 Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium
  • 30 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 31 Saw Swee Hock School of Public Health, Department of Surgery, Yong Loo Lin School of Medicine
  • 32 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
  • 33 Department of Surgery, National University Health System, Singapore, Singapore
  • 34 Department of Obstetrics and Gynecology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  • 35 Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 36 Department of Molecular Medicine and Surgery
  • 37 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
  • 38 Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 39 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
  • 40 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
  • 41 Copenhagen General Population Study, Herlev Hospital, Department of Clinical Biochemistry, Herlev Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 42 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  • 43 Department of Medical Oncology
  • 44 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 45 Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 46 Breakthrough Breast Cancer Research Centre
  • 47 London School of Hygiene and Tropical Medicine, London, UK
  • 48 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
  • 49 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 50 Institute for Medical Biometrics and Epidemiology, Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany
  • 51 Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  • 52 Department of Oncology
  • 53 Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
  • 54 CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology
  • 55 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, South Yorkshire, UK
  • 56 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 57 Department of Preventive Medicine, Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea, Cancer Research Institute, Seoul National University, Seoul, Korea
  • 58 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea, Cancer Research Institute, Seoul National University, Seoul, Korea
  • 59 Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
  • 60 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, QC, Canada
  • 61 Department of Medicine, McGill University, Montreal, QC, Canada, Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
  • 62 Département de médecine sociale et préventive, Département de santé environnementale et santé au travail, Université de Montréal, Montreal, QC, Canada
  • 63 University Breast Center Franconia, Department of Gynecology and Obstetrics, David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA
  • 64 University Breast Center Franconia, Department of Gynecology and Obstetrics
  • 65 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 66 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine
  • 67 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  • 68 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 69 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy
  • 70 Division of Cancer Studies, NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, London, UK
  • 71 Wellcome Trust Centre for Human Genetics, Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
  • 72 School of Medicine, Clinical Science Institute, National University of Ireland, Galway, Ireland
  • 73 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health
  • 74 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 75 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia, Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 76 Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 77 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  • 78 Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore
  • 79 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, College of Public Health, China Medical University, Taichong, Taiwan
  • 80 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 81 Tri-Service General Hospital, Taipei, Taiwan
  • 82 Cancer Center, Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan
  • 83 Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France, University Paris-Sud, UMRS 1018, Villejuif, France
  • 84 Inserm (National Institute of Health and Medical Research), U775, Paris, France, Centre de Ressources Biologiques EPIGENETEC, Paris, France
  • 85 Department of Medicine, Vanderbilt University, Nashville, TN, USA
  • 86 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 87 Department of Clinical Genetics
  • 88 Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  • 89 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 90 Department of Obstetrics and Gynaecology, Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 91 Department of Obstetrics and Gynaecology
  • 92 Institute of Population Health, University of Manchester, Manchester, UK, Division of Health Sciences, Warwick Medical School, Coventry, UK
  • 93 Division of Health Sciences, Warwick Medical School, Coventry, UK
  • 94 Ministry of Public Health, Thailand
  • 95 School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, Department of Clinical Pathology
  • 96 Biocenter Kuopio, School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland, Cancer Center, Kuopio University Hospital, Kuopio, Finland
  • 97 Shanghai Center for Disease Control and Prevention, Shanghai, China
  • 98 Shanghai Cancer Institute, Shanghai, China
  • 99 Department of Laboratory Medicine and Pathology, Department of Health Sciences Research
  • 100 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
  • 101 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 102 National Cancer Institute, Bangkok, Thailand
  • 103 Genetic Susceptibility Group, International Agency for Research on Cancer, Lyon, France
  • 104 Department of Laboratory Medicine and Pathology
  • 105 Department of Health Sciences Research
  • 106 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health
  • 107 University of Hawaii Cancer Center, Honolulu, HI, USA
  • 108 Department of Human Genetics and
  • 109 Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands
  • 110 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 111 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 112 Human Cancer Genetics Programme, Human Genotyping-CEGEN Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • 113 QIMR Berghofer Institute of Medical Research, Brisbane, Australia
Hum Mol Genet, 2014 Nov 15;23(22):6096-111.
PMID: 24943594 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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