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Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Darabi H 1 , Beesley J 2 , Droit A 3 , Kar S 4 , Nord S 5 , Moradi Marjaneh M 2 Show all authors , Soucy P 6 , Michailidou K 7 , Ghoussaini M 4 , Fues Wahl H 1 , Bolla MK 7 , Wang Q 7 , Dennis J 7 , Alonso MR 8 , Andrulis IL 9 , Anton-Culver H 10 , Arndt V 11 , Beckmann MW 12 , Benitez J 13 , Bogdanova NV 14 , Bojesen SE 15 , Brauch H 16 , Brenner H 11 , Broeks A 17 , Brüning T 18 , Burwinkel B 19 , Chang-Claude J 20 , Choi JY 21 , Conroy DM 4 , Couch FJ 22 , Cox A 23 , Cross SS 24 , Czene K 1 , Devilee P 25 , Dörk T 26 , Easton DF 4 , Fasching PA 12 , Figueroa J 27 , Fletcher O 28 , Flyger H 29 , Galle E 30 , García-Closas M 31 , Giles GG 32 , Goldberg MS 33 , González-Neira A 13 , Guénel P 34 , Haiman CA 35 , Hallberg E 36 , Hamann U 37 , Hartman M 38 , Hollestelle A 39 , Hopper JL 40 , Ito H 41 , Jakubowska A 42 , Johnson N 28 , Kang D 21 , Khan S 43 , Kosma VM 44 , Kriege M 39 , Kristensen V 5 , Lambrechts D 30 , Le Marchand L 45 , Lee SC 46 , Lindblom A 47 , Lophatananon A 48 , Lubinski J 42 , Mannermaa A 44 , Manoukian S 49 , Margolin S 50 , Matsuo K 51 , Mayes R 4 , McKay J 52 , Meindl A 53 , Milne RL 32 , Muir K 48 , Neuhausen SL 54 , Nevanlinna H 43 , Olswold C 36 , Orr N 28 , Peterlongo P 55 , Pita G 8 , Pylkäs K 56 , Rudolph A 20 , Sangrajrang S 57 , Sawyer EJ 58 , Schmidt MK 17 , Schmutzler RK 59 , Seynaeve C 39 , Shah M 4 , Shen CY 60 , Shu XO 61 , Southey MC 62 , Stram DO 35 , Surowy H 19 , Swerdlow A 63 , Teo SH 64 , Tessier DC 65 , Tomlinson I 66 , Torres D 37 , Truong T 34 , Vachon CM 36 , Vincent D 65 , Winqvist R 56 , Wu AH 35 , Wu PE 67 , Yip CH 68 , Zheng W 61 , Pharoah PD 4 , Hall P 1 , Edwards SL 2 , Simard J 6 , French JD 2 , Chenevix-Trench G 2 , Dunning AM 4

Affiliations 

  • 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 2 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 3 Département de Médecine Moléculaire, Faculté de Médecine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada
  • 4 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 5 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
  • 6 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada
  • 7 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 8 Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 9 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 10 Department of Epidemiology, University of California Irvine, Irvine, CA, USA
  • 11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 12 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 13 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 14 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 15 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 16 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 17 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 18 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
  • 19 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 20 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 21 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 22 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 23 Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
  • 24 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 25 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 26 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 27 Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK
  • 28 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  • 29 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 30 Vesalius Research Center, Leuven, Belgium
  • 31 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
  • 32 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • 33 Department of Medicine, McGill University, Montreal, Canada
  • 34 Cancer &Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 35 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 36 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
  • 37 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 38 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 39 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 40 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia
  • 41 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 42 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 43 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 44 Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  • 45 University of Hawaii Cancer Center, Honolulu, HI, USA
  • 46 Department of Hematology-Oncology, National University Health System, Singapore, Singapore
  • 47 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 48 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK
  • 49 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 50 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
  • 51 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 52 International Agency for Research on Cancer, Lyon, France
  • 53 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 54 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 55 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 56 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
  • 57 National Cancer Institute, Bangkok, Thailand
  • 58 Research Oncology, Guy's Hospital, King's College London, London, UK
  • 59 Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
  • 60 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 61 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  • 62 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 63 Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  • 64 Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia
  • 65 McGill University and Génome Québec Innovation Centre, Montréal, Canada
  • 66 Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
  • 67 Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 68 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
Sci Rep, 2016 Sep 07;6:32512.
PMID: 27600471 DOI: 10.1038/srep32512

Abstract

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.

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

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