DNA Methylation at Specific Loci is Associated with Overall Survival in The Cancer Genome Atlas Patients

DNA methylation influences gene expression and is altered in many cancers, but the relationship between DNA methylation and cancer outcomes is not yet fully understood. To advance our understanding of DNA methylation in cancer biology, we studied the relationship between methylation and cancer outcomes across 28 different cancer types. Using data from The Cancer Genome Atlas (TCGA), we used Cox proportional hazards regression to establish associations between methylation of individual genes and overall survival of patients in 28 studies, each examining a different cancer type. Our results showed that the numbers of genes with significant associations varied widely across studies, yet some of the genes recurred across many cancer types. The genes that recurred across cancer types were enriched for certain biological functions, including immunity and cell‐cell adhesion. There were similar numbers of genes for which methylation was associated with better survival and genes for which methylation was associated with worse survival. While these recurrent genes appeared across the entire genome, they were enriched in certain genomic regions. We also used RNA sequencing data to learn about possible mechanisms to explain the association between DNA methylation and survival. As expected, higher methylation of genes associated with survival was frequently accompanied by reduced mRNA levels. Increased methylation of genes that suppress tumor growth could contribute to worse outcomes, and increased methylation of genes that promote tumor growth could contribute to better outcomes. Ultimately, while global DNA methylation is known to be associated with outcome in certain cancers (such as prostate cancer and colorectal cancer), our results suggest that DNA methylation at specific loci also plays a role. Our work suggests that understanding patterns of localized DNA methylation is important for optimal development and use of cancer treatments.