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

Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, Beeghly-Fadiel A, Li B, Ye F, Berchuck A, Anton-Culver H, Banerjee S, Benitez J, Bjorge L, Brenton JD, Butzow R, Campbell IG, Chang-Claude J, Chen K, Cook LS, Cramer DW, Defazio A, Dennis J, Doherty JA, Doerk T, Eccles DM, Edwards DV, Fasching P, Fortner RT, Gayther SA, Giles GG, Glasspool RM, Goode EL, Goodman MT, Gronwald J, Harris HR, Heitz F, Hildebrandt MA, Hogdall E, Hogdall CK, Huntsman DG, Kar SP, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Koushik A, Lambrechts D, Le ND, Levine DA, Massuger LF, Matsuo K, May T, Mcneish IA, Menon U, Modugno F, Monteiro AN, Moorman PG, Moysich KB, Ness RB, Nevanlinna H, Olsson H, Onland-Moret NC, Park SK, Paul J, Pearce CL, Pejovic T, Phelan CM, Pike MC, Ramus SJ, Riboli E, Rodriguez-Antona C, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Shan K, Siddiqui N, Sieh W, Stampfer MJ, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Tworoger SS, Tyrer JP, Webb PM, Wentzensen N, White E, Willett WC, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long J (2019)


Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 79

Journal Issue: 3

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 x 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.

Authors with CRIS profile

Involved external institutions

Cedars-Sinai Medical Center US United States (USA) (US) University of Utah US United States (USA) (US) Vanderbilt University US United States (USA) (US) Beatson West of Scotland Cancer Centre (BWSCC) GB United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) University of Cambridge GB United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Cancer Council Victoria AU Australia (AU) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) University of California Irvine US United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) Tianjin Medical University (TMU) / 天津医科大学 CN China (CN) Duke University US United States (USA) (US) Lund University / Lunds universitet SE Sweden (SE) Danish Cancer Society Research Center DK Denmark (DK) The Institute of Cancer Research (ICR) GB United Kingdom (GB) Université de Montréal CA Canada (CA) British Columbia Cancer Agency CA Canada (CA) University of Michigan US United States (USA) (US) University Health Network (UHN) CA Canada (CA) HELIOS Kliniken DE Germany (DE) BC Cancer CA Canada (CA) Oregon Health and Science University (OSHU) US United States (USA) (US) Karolinska Institute SE Sweden (SE) National Centre for Scientific Research (NCSR) "Demokritos" GR Greece (GR) University College London (UCL) GB United Kingdom (GB) Harvard University US United States (USA) (US) University of Texas MD Anderson Cancer Center US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) University of Malaya (UM) / Universiti Malaya MY Malaysia (MY) University of Copenhagen DK Denmark (DK) Fred Hutchinson Cancer Research Center CA Canada (CA) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Glasgow Royal Infirmary (GRI) GB United Kingdom (GB) University of South Florida (USF) US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US) Peter MacCallum Cancer Centre AU Australia (AU) Hebei Medical University / 河北医科大学 CN China (CN) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) Helsingin yliopisto / University of Helsinki FI Finland (FI) Aichi Cancer Center Research Institute JP Japan (JP) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) Universiteit Utrecht (UU) / Utrecht University NL Netherlands (NL) Magee-Womens Foundation US United States (USA) (US) University of Southern California (USC) US United States (USA) (US) University of Virginia (UVA) US United States (USA) (US) Mayo Clinic US United States (USA) (US) University of Sydney (USYD) AU Australia (AU) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) Brigham and Women's Hospital (BWH) US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US) University of New South Wales (UNSW) AU Australia (AU) Medical University of South Carolina (MUSC) US United States (USA) (US) International Agency for Research on Cancer (IARC) FR France (FR) National Institute of Environmental Health Sciences (NIEHS) US United States (USA) (US) Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Roswell Park Cancer Institute US United States (USA) (US) Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust GB United Kingdom (GB) University of Southampton GB United Kingdom (GB) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) MY Malaysia (MY) University of New Mexico (UNM) / Universidad de Nuevo México US United States (USA) (US)

How to cite

APA:

Yang, Y., Wu, L., Shu, X., Lu, Y., Shu, X.-O., Cai, Q.,... Long, J. (2019). Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk. Cancer Research, 79(3). https://dx.doi.org/10.1158/0008-5472.CAN-18-2726

MLA:

Yang, Yaohua, et al. "Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk." Cancer Research 79.3 (2019).

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