Comprehensive analysis reveals common DNA methylation patterns of tobacco-associated cancers: A pan-cancer analysis

• This article explored the methylation alternations in tobacco-associated cancers. • Tobacco may reprogram cellular metabolism via regulating methylation status of related genes. • A hypomethylated enhancer region identified could be an epigenetically biomarker. • Six cluster motifs were associated with several well-known cancer hallmarks. The role of tobacco in carcinogenesis has received increasing attention across a number of disciplines in recent years. Accumulating evidences reveal that tobacco consumption affects various epigenetic modifications, especially DNA methylation. However, the genetic modifications of methylation patterns involved in tobacco-attributable cancers remain poorly understood. In this manuscript, aberrant DNA methylation patterns were investigated in 9 tobacco-attributable cancers. Differential methylated probes (DMPs) were identified in each cancer type and a total of 2,392 hyper- and 736 hypomethylated pan-cancer DMPs (PDMPs) were screened out for further analysis. PDMP-associated genes were mostly enriched in metabolism-associated pathways, suggesting the potential roles of methylation alternation in reprogramming cancer cell metabolism. Hypomethylated PDMPs cg12422154, cg02772121 and cg06051311 constituted an enhancer region, significantly downregulating TRIM15, TRIM26 and RPP21, which serve as epigenetically therapeutic biomarkers. Forty-three hypermethylated and 13 hypomethylated transcription factor motifs were clustered into 6 groups, and exhibited various biological functions. Forty-nine PDMPs were reported to be associated with prognosis, providing effective tools to predict clinical outcomes. In summary, our studies revealed the characteristics, influences and potential mechanisms of DNA methylation patterns of tobacco-attributable cancer.