Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
Authors: Yang Yaohua , Wu Lang , Shu Xiang , Lu Yingchang , Shu Xiao-Ou , Cai Qiuyin , Beeghly-Fadiel Alicia , Li Bingshan , Ye Fei , Berchuck Andrew , Anton-Culver Hoda , Banerjee Susana , Benitez Javier , Bjørge Line , Brenton James D. , Butzow Ralf , Campbell Ian G. , Chang-Claude Jenny , Chen Kexin , Cook Linda S. , Cramer Daniel W. , deFazio Anna , Dennis Joe , Doherty Jennifer A. , Dörk Thilo , Eccles Diana M. , Edwards Digna Velez , Fasching Peter A. , Fortner Renée T. , Gayther Simon A. , Giles Graham G. , Glasspool Rosalind M. , Goode Ellen L. , Goodman Marc T. , Gronwald Jacek , Harris Holly R. , Heitz Florian , Hildebrandt Michelle A. , Høgdall Estrid , Høgdall Claus K. , Huntsman David G. , Kar Siddhartha P. , Karlan Beth Y. , Kelemen Linda E. , Kiemeney Lambertus A. , Kjaer Susanne K. , Koushik Anita , Lambrechts Diether , Le Nhu D. , Levine Douglas A. , Massuger Leon F. , Matsuo Keitaro , May Taymaa , McNeish Iain A. , Menon Usha , Modugno Francesmary , Monteiro Alvaro N. , Moorman Patricia G. , Moysich Kirsten B. , Ness Roberta B. , Nevanlinna Heli , Olsson Håkan , Onland-Moret N. Charlotte , Park Sue K. , Paul James , Pearce Celeste L. , Pejovic Tanja , Phelan Catherine M. , Pike Malcolm C. , Ramus Susan J. , Riboli Elio , Rodriguez-Antona Cristina , Romieu Isabelle , Sandler Dale P. , Schildkraut Joellen M. , Setiawan Veronica W. , Shan Kang , Siddiqui Nadeem , Sieh Weiva , Stampfer Meir J. , Sutphen Rebecca , Swerdlow Anthony J. , Szafron Lukasz M. , Teo Soo Hwang , Tworoger Shelley S. , Tyrer Jonathan P. , Webb Penelope M. , Wentzensen Nicolas , White Emily , Willett Walter C. , Wolk Alicja , Woo Yin Ling , Wu Anna H. , Yan Li , Yannoukakos Drakoulis , Chenevix-Trench Georgia , Sellers Thomas A. , Pharoah Paul D.P. , Zheng Wei , Long Jirong 
Published: December 2018

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 &lt; 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.