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Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Yang Y 1 , Wu L 1 , Shu X 1 , Lu Y 1 , Shu XO 1 , Cai Q 1 Show all authors , Beeghly-Fadiel A 1 , Li B 2 , Ye F 3 , Berchuck A 4 , Anton-Culver H 5 , Banerjee S 6 , Benitez J 7 , Bjørge L 8 , Brenton JD 9 , Butzow R 10 , Campbell IG 11 , Chang-Claude J 12 , Chen K 13 , Cook LS 14 , Cramer DW 15 , deFazio A 16 , Dennis J 17 , Doherty JA 18 , Dörk T 19 , Eccles DM 20 , Edwards DV 21 , Fasching PA 22 , Fortner RT 12 , Gayther SA 23 , Giles GG 24 , Glasspool RM 25 , Goode EL 26 , Goodman MT 27 , Gronwald J 28 , Harris HR 29 , Heitz F 30 , Hildebrandt MA 31 , Høgdall E 32 , Høgdall CK 33 , Huntsman DG 34 , Kar SP 17 , Karlan BY 35 , Kelemen LE 36 , Kiemeney LA 37 , Kjaer SK 32 , Koushik A 38 , Lambrechts D 39 , Le ND 40 , Levine DA 41 , Massuger LF 42 , Matsuo K 43 , May T 44 , McNeish IA 45 , Menon U 46 , Modugno F 47 , Monteiro AN 48 , Moorman PG 49 , Moysich KB 50 , Ness RB 51 , Nevanlinna H 52 , Olsson H 53 , Onland-Moret NC 54 , Park SK 55 , Paul J 25 , Pearce CL 56 , Pejovic T 57 , Phelan CM 48 , Pike MC 58 , Ramus SJ 59 , Riboli E 60 , Rodriguez-Antona C 7 , Romieu I 61 , Sandler DP 62 , Schildkraut JM 63 , Setiawan VW 64 , Shan K 65 , Siddiqui N 66 , Sieh W 67 , Stampfer MJ 68 , Sutphen R 69 , Swerdlow AJ 70 , Szafron LM 71 , Teo SH 72 , Tworoger SS 48 , Tyrer JP 73 , Webb PM 74 , Wentzensen N 75 , White E 76 , Willett WC 15 , Wolk A 77 , Woo YL 78 , Wu AH 64 , Yan L 79 , Yannoukakos D 80 , Chenevix-Trench G 81 , Sellers TA 48 , Pharoah PDP 17 , Zheng W 1 , Long J 82

Affiliations 

  • 1 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2 Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee
  • 3 Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 4 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
  • 5 Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California
  • 6 Gynaecology Unit, Royal Marsden Hospital, London, United Kingdom
  • 7 Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • 8 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
  • 9 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  • 10 Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 11 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 12 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 13 Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
  • 14 University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico
  • 15 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 16 Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  • 17 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 18 Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
  • 19 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 20 Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
  • 21 Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 22 David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California
  • 23 The Center for Bioinformatics and Functional Genomics at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 24 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 25 The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  • 26 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota
  • 27 Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, California
  • 28 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 29 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 30 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  • 31 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 32 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 33 The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 34 Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada
  • 35 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 36 Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
  • 37 Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  • 38 CHUM Research Centre (CRCHUM) and Département de Médicine Sociale et Préventive, Université de Montréal, Montréal, Quebec, Canada
  • 39 VIB Center for Cancer Biology, VIB and Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium
  • 40 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 41 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
  • 42 Department of Gynaecology, Radboud Institute for Molecular Life sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  • 43 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 44 Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada
  • 45 Department Surgery & Cancer, Imperial College London, London, United Kingdom
  • 46 MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, United Kingdom
  • 47 Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania
  • 48 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
  • 49 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina
  • 50 Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
  • 51 School of Public Health, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas
  • 52 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 53 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
  • 54 Julius Center for Health Sciences and Primary Care, University Utrecht, UMC Utrecht, Utrecht, the Netherlands
  • 55 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 56 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan
  • 57 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon
  • 58 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
  • 59 School of Women's and Children's Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia
  • 60 Imperial College London, London, United Kingdom
  • 61 Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 62 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
  • 63 Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
  • 64 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 65 Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
  • 66 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom
  • 67 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
  • 68 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 69 Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida
  • 70 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom
  • 71 Department of Immunology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland
  • 72 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 73 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 74 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 75 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
  • 76 Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 77 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 78 Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  • 79 Department of Molecular Biology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
  • 80 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece
  • 81 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 82 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. jirong.long@vumc.org
Cancer Res, 2019 Feb 01;79(3):505-517.
PMID: 30559148 DOI: 10.1158/0008-5472.CAN-18-2726

Abstract

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

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

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