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

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

Cancer Res 2019 02 17;79(3):505-517. Epub 2018 Dec 17.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

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 ( = 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 < 7.94 × 10. 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 , and . 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.

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February 2019
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