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Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Ghoussaini M 1 , French JD 2 , Michailidou K 3 , Nord S 4 , Beesley J 2 , Canisus S 5 Show all authors , Hillman KM 2 , Kaufmann S 2 , Sivakumaran H 2 , Moradi Marjaneh M 2 , Lee JS 2 , Dennis J 6 , Bolla MK 6 , Wang Q 6 , Dicks E 1 , Milne RL 7 , Hopper JL 8 , Southey MC 9 , Schmidt MK 5 , Broeks A 5 , Muir K 10 , Lophatananon A 10 , Fasching PA 11 , Beckmann MW 12 , Fletcher O 13 , Johnson N 13 , Sawyer EJ 14 , Tomlinson I 15 , Burwinkel B 16 , Marme F 17 , Guénel P 18 , Truong T 18 , Bojesen SE 19 , Flyger H 20 , Benitez J 21 , González-Neira A 22 , Alonso MR 23 , Pita G 23 , Neuhausen SL 24 , Anton-Culver H 25 , Brenner H 26 , Arndt V 27 , Meindl A 28 , Schmutzler RK 29 , Brauch H 30 , Hamann U 31 , Tessier DC 32 , Vincent D 32 , Nevanlinna H 33 , Khan S 33 , Matsuo K 34 , Ito H 35 , Dörk T 36 , Bogdanova NV 37 , Lindblom A 38 , Margolin S 39 , Mannermaa A 40 , Kosma VM 40 , kConFab/AOCS Investigators , Wu AH 41 , Van Den Berg D 41 , Lambrechts D 42 , Floris G 43 , Chang-Claude J 44 , Rudolph A 45 , Radice P 46 , Barile M 47 , Couch FJ 48 , Hallberg E 49 , Giles GG 7 , Haiman CA 41 , Le Marchand L 50 , Goldberg MS 51 , Teo SH 52 , Yip CH 53 , Borresen-Dale AL 4 , NBCS Collaborators , Zheng W 54 , Cai Q 54 , Winqvist R 55 , Pylkäs K 55 , Andrulis IL 56 , Devilee P 57 , Tollenaar RA 58 , García-Closas M 59 , Figueroa J 60 , Hall P 61 , Czene K 61 , Brand JS 61 , Darabi H 61 , Eriksson M 61 , Hooning MJ 62 , Koppert LB 63 , Li J 61 , Shu XO 54 , Zheng Y 64 , Cox A 65 , Cross SS 66 , Shah M 1 , Rhenius V 1 , Choi JY 67 , Kang D 68 , Hartman M 69 , Chia KS 70 , Kabisch M 31 , Torres D 71 , Luccarini C 1 , Conroy DM 1 , Jakubowska A 72 , Lubinski J 72 , Sangrajrang S 73 , Brennan P 74 , Olswold C 50 , Slager S 50 , Shen CY 75 , Hou MF 76 , Swerdlow A 77 , Schoemaker MJ 78 , Simard J 79 , Pharoah PD 80 , Kristensen V 81 , Chenevix-Trench G 2 , Easton DF 80 , Dunning AM 82 , Edwards SL 83

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
  • 2 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 1683, Cyprus
  • 4 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0310 Oslo, Norway
  • 5 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
  • 6 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
  • 7 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, VIC 3010, Australia
  • 8 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, VIC 3010, Australia
  • 9 Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia
  • 10 Institute of Population Health, University of Manchester, Manchester M13 9PL, UK; Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK
  • 11 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA
  • 12 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  • 13 Toby Robins Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
  • 14 Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK
  • 15 Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK
  • 16 Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany; Molecular Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 17 Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
  • 18 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807 Villejuif, France
  • 19 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
  • 20 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  • 21 Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain; Centro de Investigación en Red de Enfermedades Raras, 46010 Valencia, Spain
  • 22 Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
  • 23 Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
  • 24 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA 92697, USA
  • 25 Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA
  • 26 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
  • 27 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 28 Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany
  • 29 Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, 50931 Cologne, Germany; Center for Integrated Oncology (CIO), University Hospital of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
  • 30 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany; University of Tübingen, 72074 Tübingen, Germany
  • 31 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 32 McGill University and Génome Québec Innovation Centre, Montréal, QC H3A OG1, Canada
  • 33 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00029 Helsinki, Finland
  • 34 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
  • 35 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
  • 36 Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
  • 37 Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany; Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany
  • 38 Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
  • 39 Department of Oncology-Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
  • 40 Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland
  • 41 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
  • 42 Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium
  • 43 University Hospital Gashuisberg, 3000 Leuven, Belgium
  • 44 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
  • 45 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 46 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), 20133 Milan, Italy
  • 47 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, 20141 Milan, Italy
  • 48 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
  • 49 Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
  • 50 University of Hawaii Cancer Center, Honolulu, HI 96813, USA
  • 51 Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada; Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, QC H3A 1A8, Canada
  • 52 Cancer Research Initiatives Foundation, Subang Jaya, 47500 Selangor, Malaysia; Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia
  • 53 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia
  • 54 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
  • 55 Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90220 Oulu, Finland
  • 56 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
  • 57 Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
  • 58 Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
  • 59 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
  • 60 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh EH8 9AG, UK
  • 61 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden
  • 62 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3008 AE Rotterdam, the Netherlands
  • 63 Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3008 AE Rotterdam, the Netherlands
  • 64 Shanghai Municipal Center for Disease Control and Prevention, 200336 Shanghai, China
  • 65 Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK
  • 66 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
  • 67 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea; Cancer Research Institute, Seoul National University, Seoul 110-799, Korea
  • 68 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea; Cancer Research Institute, Seoul National University, Seoul 110-799, Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea
  • 69 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Department of Surgery, National University Health System, Singapore 117597, Singapore
  • 70 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore
  • 71 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, DC 11001000, Colombia
  • 72 Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
  • 73 National Cancer Institute, Bangkok 10400, Thailand
  • 74 International Agency for Research on Cancer, Lyon Cedex 08, France
  • 75 School of Public Health, China Medical University, Taichung 40402, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
  • 76 Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
  • 77 Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK; Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
  • 78 Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK
  • 79 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC G1V 4G2, Canada
  • 80 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
  • 81 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0310 Oslo, Norway; Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 0450 Oslo, Norway
  • 82 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK. Electronic address: amd24@medschl.cam.ac.uk
  • 83 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: stacey.edwards@qimrberghofer.edu.au
Am J Hum Genet, 2016 Oct 06;99(4):903-911.
PMID: 27640304 DOI: 10.1016/j.ajhg.2016.07.017

Abstract

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

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

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