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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Lu Y 1 , Beeghly-Fadiel A 1 , Wu L 1 , Guo X 1 , Li B 2 , Schildkraut JM 3 Show all authors , Im HK 4 , Chen YA 5 , Permuth JB 6 , Reid BM 6 , Teer JK 5 , Moysich KB 7 , Andrulis IL 8 , Anton-Culver H 9 , Arun BK 10 , Bandera EV 11 , Barkardottir RB 12 , Barnes DR 13 , Benitez J 14 , Bjorge L 15 , Brenton J 16 , Butzow R 17 , Caldes T 18 , Caligo MA 19 , Campbell I 20 , Chang-Claude J 21 , Claes KBM 22 , Couch FJ 23 , Cramer DW 24 , Daly MB 25 , deFazio A 26 , Dennis J 13 , Diez O 27 , Domchek SM 28 , Dörk T 29 , Easton DF 13 , Eccles DM 30 , Fasching PA 31 , Fortner RT 21 , Fountzilas G 32 , Friedman E 33 , Ganz PA 34 , Garber J 35 , Giles GG 36 , Godwin AK 37 , Goldgar DE 38 , Goodman MT 39 , Greene MH 40 , Gronwald J 41 , Hamann U 42 , Heitz F 43 , Hildebrandt MAT 44 , Høgdall CK 45 , Hollestelle A 46 , Hulick PJ 47 , Huntsman DG 48 , Imyanitov EN 49 , Isaacs C 50 , Jakubowska A 41 , James P 51 , Karlan BY 52 , Kelemen LE 53 , Kiemeney LA 54 , Kjaer SK 55 , Kwong A 56 , Le ND 57 , Leslie G 13 , Lesueur F 58 , Levine DA 59 , Mattiello A 60 , May T 61 , McGuffog L 13 , McNeish IA 62 , Merritt MA 63 , Modugno F 64 , Montagna M 65 , Neuhausen SL 66 , Nevanlinna H 67 , Nielsen FC 68 , Nikitina-Zake L 69 , Nussbaum RL 70 , Offit K 71 , Olah E 72 , Olopade OI 73 , Olson SH 74 , Olsson H 75 , Osorio A 14 , Park SK 76 , Parsons MT 77 , Peeters PHM 78 , Pejovic T 79 , Peterlongo P 80 , Phelan CM 6 , Pujana MA 81 , Ramus SJ 82 , Rennert G 83 , Risch H 84 , Rodriguez GC 85 , Rodríguez-Antona C 86 , Romieu I 87 , Rookus MA 88 , Rossing MA 89 , Rzepecka IK 90 , Sandler DP 91 , Schmutzler RK 92 , Setiawan VW 93 , Sharma P 94 , Sieh W 95 , Simard J 96 , Singer CF 97 , Song H 98 , Southey MC 99 , Spurdle AB 77 , Sutphen R 100 , Swerdlow AJ 101 , Teixeira MR 102 , Teo SH 103 , Thomassen M 104 , Tischkowitz M 105 , Toland AE 106 , Trichopoulou A 107 , Tung N 108 , Tworoger SS 6 , van Rensburg EJ 109 , Vanderstichele A 110 , Vega A 111 , Edwards DV 112 , Webb PM 113 , Weitzel JN 114 , Wentzensen N 115 , White E 116 , Wolk A 117 , Wu AH 93 , Yannoukakos D 118 , Zorn KK 119 , Gayther SA 93 , Antoniou AC 13 , Berchuck A 120 , Goode EL 121 , Chenevix-Trench G 77 , Sellers TA 6 , Pharoah PDP 13 , Zheng W 1 , Long J 122

Affiliations 

  • 1 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 2 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 3 Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
  • 4 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois
  • 5 Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida
  • 6 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
  • 7 Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
  • 8 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 9 Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California
  • 10 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 11 Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
  • 12 Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland
  • 13 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 14 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 15 Department of Gynecology and Obstetrics, Haukeland University Horpital, Bergen, Norway
  • 16 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  • 17 Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 18 Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
  • 19 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy
  • 20 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 21 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 22 Centre for Medical Genetics, Ghent University, Gent, Belgium
  • 23 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 24 Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts
  • 25 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 26 Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  • 27 Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d'Hebron Institute of Oncology (VHIO), University Hospital, Vall d'Hebron, Barcelona, Spain
  • 28 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
  • 29 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 30 Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
  • 31 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 32 Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
  • 33 The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
  • 34 Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, California
  • 35 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 36 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 37 Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, Kansas
  • 38 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah
  • 39 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 40 Clinical Genetics Branch, DCEG, National Cancer Institute, Bethesda, Maryland
  • 41 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 42 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 43 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  • 44 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 45 Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 46 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 47 Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois
  • 48 British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada
  • 49 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 50 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
  • 51 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  • 52 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 53 Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
  • 54 Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • 55 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 56 Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong
  • 57 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 58 Genetic Epidemiology of Cancer team, Inserm U900, Paris, France
  • 59 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
  • 60 Dipertimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy
  • 61 Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada
  • 62 Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom
  • 63 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
  • 64 Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
  • 65 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
  • 66 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California
  • 67 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 68 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 69 Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 70 Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, California
  • 71 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 72 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 73 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois
  • 74 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 75 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
  • 76 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 77 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 78 Julius Center for Health Sciences and Primary Care, UMC Utrecht, University Utrecht, Utrecht, The Netherlands
  • 79 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon
  • 80 IFOM, the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 81 Catalan Institute of Oncology, ProCURE, Oncobell, Bellvitge Biomedical Research Institute (IDIBELL). Barcelona, Spain
  • 82 School of Women's and Children's Health, University of NSW Sydney, Sydney, New South Wales, Australia
  • 83 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
  • 84 School of Public Health, Yale University, New Haven, Connecticut
  • 85 Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, Illinois
  • 86 Hereditary Endocrine Cancer group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
  • 87 Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 88 Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  • 89 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 90 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 91 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Maryland
  • 92 Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
  • 93 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 94 Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas
  • 95 Department of Genetics and Genomic Sciences, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
  • 96 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec, Canada
  • 97 Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 98 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 99 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 100 Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida
  • 101 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
  • 102 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 103 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 104 Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark
  • 105 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada
  • 106 Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • 107 Hellenic Health Foundation, Athens, Greece
  • 108 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 109 Department of Genetics, University of Pretoria, Arcadia, South Africa
  • 110 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  • 111 Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain
  • 112 Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 113 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 114 Clinical Cancer Genetics, City of Hope, Duarte, California
  • 115 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
  • 116 Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 117 Department of Environmental Medicine, Division of Nutritional Epidemiology, Karolinska Institutet, Stockholm, Sweden
  • 118 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 119 Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 120 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
  • 121 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 122 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. jirong.long@vanderbilt.edu
Cancer Res, 2018 Sep 15;78(18):5419-5430.
PMID: 30054336 DOI: 10.1158/0008-5472.CAN-18-0951

Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

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

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