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Cancer Res. 2019 Feb 1;79(3):505-517. doi: 10.1158/0008-5472.CAN-18-2726. Epub 2018 Dec 17.

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

Author information

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
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
9
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
10
Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
11
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
12
Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
13
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
14
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
15
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
16
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
17
Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
18
University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico.
19
Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada.
20
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
21
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
22
Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
23
Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
24
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
25
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
26
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
27
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
28
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee.
29
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California.
30
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
31
The Center for Bioinformatics and Functional Genomics at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
32
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
33
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
34
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
35
The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
36
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.
37
Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, California.
38
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
39
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
40
Department of Epidemiology, University of Washington, Seattle, Washington.
41
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
42
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
43
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
44
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
45
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
46
The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
47
Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
48
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
49
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
50
OVCARE, Vancouver Coastal Health Research Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
51
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
52
Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
53
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
54
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
55
CHUM Research Centre (CRCHUM) and Département de Médicine Sociale et Préventive, Université de Montréal, Montréal, Quebec, Canada.
56
VIB Center for Cancer Biology, VIB and Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
57
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
58
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
59
Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
60
Department of Gynaecology, Radboud Institute for Molecular Life sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
61
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
62
Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
63
Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada.
64
Department Surgery & Cancer, Imperial College London, London, United Kingdom.
65
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, United Kingdom.
66
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, United Kingdom.
67
Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania.
68
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
69
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
70
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina.
71
Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
72
School of Public Health, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas.
73
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
74
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
75
Julius Center for Health Sciences and Primary Care, University Utrecht, UMC Utrecht, Utrecht, the Netherlands.
76
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
77
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
78
Cancer Research Institute, Seoul National University, Seoul, Korea.
79
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.
80
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
81
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon.
82
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
83
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
84
School of Women's and Children's Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia.
85
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
86
Imperial College London, London, United Kingdom.
87
Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
88
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
89
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
90
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
91
Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China.
92
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
93
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
94
Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.
95
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
96
Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida.
97
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
98
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
99
Department of Immunology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.
100
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
101
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
102
Research Institute and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
103
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
104
Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
105
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
106
Fred Hutchinson Cancer Research Center, Seattle, Washington.
107
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
108
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
109
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
110
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
111
Department of Molecular Biology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China.
112
Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece.
113
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
114
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. jirong.long@vumc.org.

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.

PMID:
30559148
PMCID:
PMC6359948
[Available on 2020-02-01]
DOI:
10.1158/0008-5472.CAN-18-2726

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