Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Glubb DM 1 , Thompson DJ 2 , Aben KKH 3 , Alsulimani A 4 , Amant F 5 , Annibali D 5 Show all authors , Attia J 6 , Barricarte A 7 , Beckmann MW 8 , Berchuck A 9 , Bermisheva M 10 , Bernardini MQ 11 , Bischof K 12 , Bjorge L 12 , Bodelon C 13 , Brand AH 14 , Brenton JD 15 , Brinton LA 13 , Bruinsma F 16 , Buchanan DD 17 , Burghaus S 8 , Butzow R 18 , Cai H 19 , Carney ME 20 , Chanock SJ 21 , Chen C 22 , Chen XQ 1 , Chen Z 23 , Cook LS 24 , Cunningham JM 25 , De Vivo I 26 , deFazio A 14 , Doherty JA 27 , Dörk T 28 , du Bois A 29 , Dunning AM 30 , Dürst M 31 , Edwards T 32 , Edwards RP 33 , Ekici AB 34 , Ewing A 2 , Fasching PA 8 , Ferguson S 11 , Flanagan JM 35 , Fostira F 36 , Fountzilas G 37 , Friedenreich CM 38 , Gao B 39 , Gaudet MM 40 , Gawełko J 41 , Gentry-Maharaj A 42 , Giles GG 16 , Glasspool R 43 , Goodman MT 44 , Gronwald J 45 , Harris HR 46 , Harter P 29 , Hein A 8 , Heitz F 29 , Hildebrandt MAT 47 , Hillemanns P 28 , Høgdall E 48 , Høgdall CK 49 , Holliday EG 6 , Huntsman DG 50 , Huzarski T 51 , Jakubowska A 45 , Jensen A 48 , Jones ME 52 , Karlan BY 53 , Karnezis A 54 , Kelley JL 55 , Khusnutdinova E 10 , Killeen JL 56 , Kjaer SK 48 , Klapdor R 57 , Köbel M 58 , Konopka B 59 , Konstantopoulou I 36 , Kopperud RK 12 , Koti M 60 , Kraft P 61 , Kupryjanczyk J 59 , Lambrechts D 62 , Larson MC 63 , Le Marchand L 64 , Lele S 65 , Lester J 53 , Li AJ 66 , Liang D 67 , Liebrich C 68 , Lipworth L 69 , Lissowska J 70 , Lu L 71 , Lu KH 72 , Macciotta A 73 , Mattiello A 74 , May T 11 , McAlpine JN 75 , McGuire V 76 , McNeish IA 77 , Menon U 42 , Modugno F 55 , Moysich KB 4 , Nevanlinna H 78 , Odunsi K 65 , Olsson H 79 , Orsulic S 66 , Osorio A 80 , Palli D 81 , Park-Simon TW 28 , Pearce CL 82 , Pejovic T 83 , Permuth JB 84 , Podgorska A 59 , Ramus SJ 85 , Rebbeck TR 86 , Riggan MJ 9 , Risch HA 71 , Rothstein JH 87 , Runnebaum IB 31 , Scott RJ 6 , Sellers TA 84 , Senz J 50 , Setiawan VW 88 , Siddiqui N 89 , Sieh W 87 , Spiewankiewicz B 90 , Sutphen R 91 , Swerdlow AJ 52 , Szafron LM 92 , Teo SH 93 , Thompson PJ 44 , Thomsen LCV 12 , Titus L 94 , Tone A 11 , Tumino R 95 , Turman C 61 , Vanderstichele A 96 , Edwards DV 97 , Vergote I 96 , Vierkant RA 63 , Wang Z 13 , Wang-Gohrke S 98 , Webb PM 99 , OPAL Study Group , AOCS Group , White E 100 , Whittemore AS 76 , Winham SJ 63 , Wu X 47 , Wu AH 88 , Yannoukakos D 36 , Spurdle AB 1 , O'Mara TA 101

Affiliations 

  • 1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 2 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 3 Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  • 4 Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
  • 5 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium
  • 6 Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia
  • 7 CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • 8 Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 9 Department of Gynecologic Oncology, Duke University Hospital, Durham, North Carolina
  • 10 Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
  • 11 Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada
  • 12 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
  • 13 Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland
  • 14 Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
  • 15 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
  • 16 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 17 Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 18 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 19 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 20 John A. Burns School of Medicine, Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, Hawaii
  • 21 Division of Cancer Epidemiology and Genetics, NCI, NIH, Department of Health and Human Services, Bethesda, Maryland
  • 22 Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 23 Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida
  • 24 University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico
  • 25 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 26 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 27 Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
  • 28 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 29 Department of Gynecology and Gynecologic Oncology, Ev. Kliniken Essen-Mitte (KEM), Essen, Germany
  • 30 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 31 Department of Gynaecology, Jena University Hospital- Friedrich Schiller University, Jena, Germany
  • 32 Division of Epidemiology, Center for Human Genetics Research, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 33 Ovarian Cancer Center of Excellence, Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
  • 34 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 35 Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK
  • 36 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens, Greece
  • 37 Second Department of Medical Oncology, EUROMEDICA General Clinic of Thessaloniki, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
  • 38 Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada
  • 39 Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  • 40 Department of Population Science, American Cancer Society, Atlanta, Georgia
  • 41 Institute of Nursing and Health Sciences, Medical Faculty, University of Rzeszów, Rzeszów, Poland
  • 42 MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
  • 43 Department of Medical Oncology, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK
  • 44 Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, California
  • 45 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 46 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 47 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 48 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 49 The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 50 British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada
  • 51 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
  • 52 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 53 David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California
  • 54 Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, California
  • 55 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 56 Department of Pathology, Kapiolani Medical Center for Women and Children, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
  • 57 Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
  • 58 Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada
  • 59 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  • 60 Departments of Biomedical and Molecular Sciences and Obstetrics and Gynaecology, Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
  • 61 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 62 VIB Center for Cancer Biology, Leuven, Belgium
  • 63 Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
  • 64 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
  • 65 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York
  • 66 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 67 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas
  • 68 Clinics of Gynaecology, Cancer Center Wolfsburg, Wolfsburg, Germany
  • 69 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 70 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland
  • 71 Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
  • 72 Department of Gynecologic Oncology and Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 73 Evangelische Kliniken Essen-Mitte Klinik für Gynäkologie und gynäkologische Onkologie, Essen, Germany
  • 74 Dipertimento Di Medicina Clinca e Chirurgia, Federico II University, Naples, Italy
  • 75 British Columbia's Ovarian Cancer Research (OVCARE) Program-Gynecologic Tissue Bank, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver General Hospital and BC Cancer, Vancouver, BC, Canada
  • 76 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California
  • 77 Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery and Cancer, Imperial College London, London, UK
  • 78 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 79 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
  • 80 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 81 Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
  • 82 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan
  • 83 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon
  • 84 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
  • 85 School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia
  • 86 Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 87 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
  • 88 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 89 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK
  • 90 Tytus Chałbiński Specialist Hospital in Radom, Warsaw, Poland
  • 91 Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida
  • 92 Department of Immunology, the Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland
  • 93 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 94 Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire
  • 95 Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Berlin, Germany
  • 96 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  • 97 Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Department of Biomedical Sciences, Women's Health Research, Vanderbilt University Medical Center, Nashville, Tennessee
  • 98 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 99 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 100 Department of Epidemiology, University of Washington, Seattle, Washington
  • 101 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. [email protected]
Cancer Epidemiol Biomarkers Prev, 2021 Jan;30(1):217-228.
PMID: 33144283 DOI: 10.1158/1055-9965.EPI-20-0739

Abstract

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

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

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