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Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

Glubb DM 1 , Maranian MJ 2 , Michailidou K 3 , Pooley KA 2 , Meyer KB 4 , Kar S 3 Show all authors , Carlebur S 4 , O'Reilly M 4 , Betts JA 5 , Hillman KM 1 , Kaufmann S 1 , Beesley J 1 , Canisius S 6 , Hopper JL 7 , Southey MC 8 , Tsimiklis H 8 , Apicella C 8 , Schmidt MK 6 , Broeks A 6 , Hogervorst FB 6 , van der Schoot CE 9 , Muir K 10 , Lophatananon A 11 , Stewart-Brown S 11 , Siriwanarangsan P 12 , Fasching PA 13 , Ruebner M 14 , Ekici AB 15 , Beckmann MW 14 , Peto J 16 , dos-Santos-Silva I 16 , Fletcher O 17 , Johnson N 17 , Pharoah PD 18 , Bolla MK 3 , Wang Q 3 , Dennis J 3 , Sawyer EJ 19 , Tomlinson I 20 , Kerin MJ 21 , Miller N 21 , Burwinkel B 22 , Marme F 23 , Yang R 24 , Surowy H 24 , Guénel P 25 , Truong T 25 , Menegaux F 25 , Sanchez M 25 , Bojesen SE 26 , Nordestgaard BG 26 , Nielsen SF 27 , Flyger H 28 , González-Neira A 29 , Benitez J 30 , Zamora MP 31 , Arias Perez JI 32 , Anton-Culver H 33 , Neuhausen SL 34 , Brenner H 35 , Dieffenbach AK 35 , Arndt V 36 , Stegmaier C 37 , Meindl A 38 , Schmutzler RK 39 , Brauch H 40 , Ko YD 41 , Brüning T 42 , GENICA Network , Nevanlinna H 43 , Muranen TA 43 , Aittomäki K 44 , Blomqvist C 45 , Matsuo K 46 , Ito H 47 , Iwata H 48 , Tanaka H 47 , Dörk T 49 , Bogdanova NV 50 , Helbig S 49 , Lindblom A 51 , Margolin S 52 , Mannermaa A 53 , Kataja V 54 , Kosma VM 53 , Hartikainen JM 53 , kConFab Investigators , Wu AH 55 , Tseng CC 55 , Van Den Berg D 55 , Stram DO 55 , Lambrechts D 56 , Zhao H 56 , Weltens C 57 , van Limbergen E 57 , Chang-Claude J 58 , Flesch-Janys D 59 , Rudolph A 58 , Seibold P 58 , Radice P 60 , Peterlongo P 61 , Barile M 62 , Capra F 63 , Couch FJ 64 , Olson JE 65 , Hallberg E 65 , Vachon C 65 , Giles GG 66 , Milne RL 66 , McLean C 67 , Haiman CA 55 , Henderson BE 55 , Schumacher F 55 , Le Marchand L 68 , Simard J 69 , Goldberg MS 70 , Labrèche F 71 , Dumont M 69 , Teo SH 72 , Yip CH 73 , See MH 73 , Cornes B 74 , Cheng CY 74 , Ikram MK 74 , Kristensen V 75 , Norwegian Breast Cancer Study , Zheng W 76 , Halverson SL 76 , Shrubsole M 76 , Long J 76 , Winqvist R 77 , Pylkäs K 77 , Jukkola-Vuorinen A 78 , Kauppila S 79 , Andrulis IL 80 , Knight JA 81 , Glendon G 82 , Tchatchou S 82 , Devilee P 83 , Tollenaar RA 83 , Seynaeve C 84 , Van Asperen CJ 85 , García-Closas M 86 , Figueroa J 87 , Chanock SJ 87 , Lissowska J 88 , Czene K 89 , Klevebring D 89 , Darabi H 89 , Eriksson M 89 , Hooning MJ 90 , Hollestelle A 90 , Martens JW 90 , Collée JM 91 , Hall P 89 , Li J 92 , Humphreys K 89 , Shu XO 76 , Lu W 93 , Gao YT 94 , Cai H 76 , Cox A 95 , Cross SS 96 , Reed MW 95 , Blot W 97 , Signorello LB 97 , Cai Q 76 , Shah M 2 , Ghoussaini M 2 , Kang D 98 , Choi JY 99 , Park SK 98 , Noh DY 100 , Hartman M 101 , Miao H 102 , Lim WY 102 , Tang A 103 , Hamann U 104 , Torres D 105 , Jakubowska A 106 , Lubinski J 106 , Jaworska K 106 , Durda K 106 , Sangrajrang S 107 , Gaborieau V 108 , Brennan P 108 , McKay J 108 , Olswold C 65 , Slager S 65 , Toland AE 109 , Yannoukakos D 110 , Shen CY 111 , Wu PE 112 , Yu JC 113 , Hou MF 114 , Swerdlow A 115 , Ashworth A 17 , Orr N 17 , Jones M 116 , Pita G 29 , Alonso MR 29 , Álvarez N 29 , Herrero D 29 , Tessier DC 117 , Vincent D 117 , Bacot F 117 , Luccarini C 2 , Baynes C 2 , Ahmed S 2 , Healey CS 2 , Brown MA 118 , Ponder BA 4 , Chenevix-Trench G 1 , Thompson DJ 3 , Edwards SL 5 , Easton DF 18 , Dunning AM 119 , French JD 120

Affiliations 

  • 1 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
  • 2 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
  • 4 Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
  • 5 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
  • 6 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
  • 7 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3010, Australia
  • 8 Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
  • 9 Sanquin Research, 1066 CX Amsterdam, the Netherlands
  • 10 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK; Institute of Population Health, University of Manchester, Manchester M13 9PL, UK
  • 11 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK
  • 12 Ministry of Public Health, Nonthaburi 11000, Thailand
  • 13 University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany; Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  • 14 University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  • 15 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  • 16 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
  • 17 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
  • 18 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
  • 19 Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK
  • 20 Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford OX3 7BN, UK
  • 21 Clinical Science Institute, University Hospital Galway, Galway, Ireland
  • 22 Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany
  • 23 Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
  • 24 Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany; Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
  • 25 Institut National de la Santé et de la Recherche Médicale U1018, Environmental Epidemiology of Cancers, Centre de Recherche en Epidémiologie et Santé des Populations, 94807 Villejuif, France; UMRS 1018, University Paris-Sud, 94807 Villejuif, France
  • 26 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
  • 27 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  • 28 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  • 29 Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
  • 30 Centro de Investigación en Red de Enfermedades Raras, 46010 Valencia, Spain; Human Genetics Group, Spanish National Cancer Centre and Biomedical Network on Rare Diseases, 28029 Madrid, Spain
  • 31 Servicio de Oncología Médica, Hospital Universitario La Paz, 28029 Madrid, Spain
  • 32 Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, 33012 Oviedo, Spain
  • 33 Department of Epidemiology, University of California, Irvine, Irvine, CA 92697, USA
  • 34 Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
  • 35 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, 69120 Heidelberg, Germany; German Cancer Consortium, 69120 Heidelberg, Germany
  • 36 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, 69120 Heidelberg, Germany
  • 37 Saarland Cancer Registry, 66024 Saarbrücken, Germany
  • 38 Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany
  • 39 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50931 Cologne, Germany; Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology, Center for Molecular Medicine Cologne, University Hospital of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50923 Cologne, Germany; Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, 50937 Cologne, Germany
  • 40 University of Tübingen, 72074 Tübingen, Germany; Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany
  • 41 Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113 Bonn, Germany
  • 42 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, 44789 Bochum, Germany
  • 43 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland
  • 44 Department of Clinical Genetics, Helsinki University Central Hospital, 00029 Helsinki, Finland
  • 45 Department of Oncology, University of Helsinki and Helsinki University Central Hospital, 00029 Helsinki, Finland
  • 46 Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
  • 47 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
  • 48 Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
  • 49 Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
  • 50 Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany
  • 51 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden
  • 52 Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
  • 53 Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland
  • 54 Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland; Cancer Center, Kuopio University Hospital, 70211 Kuopio, Finland
  • 55 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
  • 56 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium; Vesalius Research Center, VIB, 3000 Leuven, Belgium
  • 57 University Hospital Gashuisberg, 3000 Leuven, Belgium
  • 58 Division of Cancer Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
  • 59 Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, 20246 Hamburg, Germany
  • 60 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Istituto Nazionale Tumori, Fondazione Istituto Neurologico Carlo Besta, 20133 Milan, Italy
  • 61 Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy
  • 62 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, 20141 Milan, Italy
  • 63 Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy; Cogentech Cancer Genetic Test Laboratory, 20139 Milan, Italy
  • 64 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
  • 65 Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
  • 66 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia
  • 67 Anatomical Pathology, The Alfred, Melbourne, VIC 3004, Australia
  • 68 University of Hawaii Cancer Centre Honolulu, HI 96813, USA
  • 69 Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1V 4G2, Canada
  • 70 Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada; Department of Medicine, McGill University, Montreal, QC H3A 1A1, Canada
  • 71 Département de Médecine Sociale et Préventive, Département de Santé Environnementale et Santé au Travail, Université de Montréal, Montreal, QC H3A 3C2, Canada
  • 72 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia; Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
  • 73 Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
  • 74 Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore
  • 75 Institute of Clinical Medicine, University of Oslo, 0450 Oslo, Norway; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway; Department of Clinical Molecular Biology, University of Oslo, 0450 Oslo, Norway
  • 76 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
  • 77 Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu University Hospital, 90210 Oulu, Finland
  • 78 Department of Oncology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
  • 79 Department of Pathology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
  • 80 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada
  • 81 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
  • 82 Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
  • 83 Departments of Human Genetics and Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
  • 84 Family Cancer Clinic, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
  • 85 Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
  • 86 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK; Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK
  • 87 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA
  • 88 Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland
  • 89 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
  • 90 Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, 3075 EA Rotterdam, the Netherlands
  • 91 Department of Clinical Genetics, Erasmus University Medical Center, 3008 AE Rotterdam, the Netherlands
  • 92 Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore
  • 93 Shanghai Center for Disease Control and Prevention, Changning, Shanghai 200336, China
  • 94 Department of Epidemiology, Shanghai Cancer Institute, Shanghai 200032, China
  • 95 Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK
  • 96 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2RX, UK
  • 97 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA; International Epidemiology Institute, Rockville, MD 20850, USA
  • 98 Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul 110-799, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
  • 99 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
  • 100 Department of Surgery, Seoul National University, Bundang Hospital, Seongnam 110-744, Korea
  • 101 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore 119228, Singapore
  • 102 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore
  • 103 Division of General Surgery, National University Health System, Singapore 119228, Singapore
  • 104 Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
  • 105 Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Institute of Human Genetics, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia
  • 106 Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
  • 107 National Cancer Institute, Bangkok 10400, Thailand
  • 108 International Agency for Research on Cancer, 69372 Lyon, France
  • 109 Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210, USA
  • 110 Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research "Demokritos," Aghia Paraskevi Attikis, Athens 15310, Greece
  • 111 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Public Health, China Medical University, Taichung 40402, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
  • 112 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
  • 113 Department of Surgery, Tri-Service General Hospital, Taipei 114, Taiwan
  • 114 Cancer Center and Department of Surgery, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung 807, Taiwan
  • 115 Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK; Division of Breast Cancer Research, Institute of Cancer Research, Sutton SM2 5NG, UK
  • 116 Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK
  • 117 McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada
  • 118 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
  • 119 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK. Electronic address: amd24@medschl.cam.ac.uk
  • 120 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: juliet.french@qimrberghofer.edu.au
Am J Hum Genet, 2015 Jan 08;96(1):5-20.
PMID: 25529635 DOI: 10.1016/j.ajhg.2014.11.009

Abstract

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

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

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