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

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 ¼ 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 Â 10 À7 . 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, ARH-GAP27, 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.

An integrative multi-omics network-based approach identifies key regulators for breast cancer

“…CDK6 and MLLT10 have been identified as cancer driver genes according to the COSMIC database. By manually checking in the PubMed, 7 of the top 20 genes were reported to be relevant to ovarian cancer, including MAPT [55] , BECN1 [56] , PRC1 [57] , CBX1 [58] , CDK6 [59] , WWOX [60] , and PNPO [61] . We performed KEGG pathway enrichment analysis for the top 100 genes ( Figure Supplementary Fig.…”

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

“…For each CpG site, we built a genetic model to predict DNA methylation levels using the elastic net method as implemented in the “glmnet” package of R, with α = 0.5 39 – 41 (Supplementary Software 1 ). Genetic variants flanking a 2-Mb window of each CpG site were used to build the model.…”

Methylation in HOX Clusters and Its Applications in Cancer Therapy

“…HOXB3 and HOXB4 hypermethylation were identified as potential biomarkers in lung adenocarcinoma diagnosis [80]. In addition, data from nearly 63,000 women of European ancestry suggest that HOXB3 hypermethylation is among the epigenetic modifications associated with epithelial ovarian cancer risk [113], and that HOXB4 is part of a multigene methylation signature found in circulating tumor cells from patients with metastatic breast cancer [46]. Among HOXB genes, HOXB13 is frequently identified as being hypermethylated in tumors.…”