Integrative pan-cancer analysis reveals a common architecture of dysregulated transcriptional networks characterized by loss of enhancer methylation

Aberrant DNA methylation contributes to gene expression deregulation in cancer. However, these alterations’ precise regulatory role and clinical implications are still not fully understood. In this study, we performed expression-methylation Quantitative Trait Loci (emQTL) analysis to identify deregulated cancer-driving transcriptional networks linked to CpG demethylation pan-cancer. By analyzing 33 cancer types from The Cancer Genome Atlas, we identified and confirmed significant correlations between CpG methylation and gene expression (emQTL) in cis and trans , both across and within cancer types. Bipartite network analysis of the emQTL revealed groups of CpGs and genes related to important biological processes involved in carcinogenesis; specifically, we identified three types of emQTL networks associated with alterations linked to the regulation of proliferation, metabolism, and hormone-signaling. These bipartite communities were characterized by loss of enhancer methylation in transcription factor binding regions (TFBRs) located in enhancers. The underlying CpGs were topologically linked to upregulated genes through chromatin loops. Loss of enhancer methylation and target genes were exemplified in pancreatic cancer. Penalized Cox regression analysis showed a significant prognostic impact of the pan-cancer emQTL. Taken together, our integrative pan-cancer analysis reveals a common architecture of aberrant DNA demethylation that illustrates a convergence of pathological regulatory mechanisms across cancer types. ### Competing Interest Statement The authors have declared no competing interest. * AR : Androgen receptor ASCAT : Allele-Specific Copy Number Analysis of Tumors BH : Benjamini-Hochberg BRCA : Breast invasive carcinoma ChIA-PET : Chromatin Interaction Analysis with Paired-End Tag dELS : TSS-distal enhancer-like signatures DNMT : DNA methyltransferase emQTL : Expression-methylation Quantitative Trait Loci Analysis ENCODE : The Encyclopedia of DNA Elements EMT : epithelial-mesenchymal transition ESR1 : Estrogen receptor alpha FE : Fold enrichment FOXA1 : Forkhead Box A1 GATA : GATA binding protein 2 GEO : Gene Expression Omnibus GSEA : Gene set enrichment analysis IM-PET : Integrated Methods for Predicting Enhancer Targets NCI : National Cancer Institute PAAD : Pancreatic adenocarcinoma PCA : Principal component analysis PC : Principal component PDAC : Pancreatic ductal adenocarcinoma pELS : TSS-proximal enhancer-like signatures PLS : promoter-like signatures TCGA : The Cancer Genome Atlas TET : Ten-eleven translocation TF : Transcription factor TFBR : Transcription factor binding region TFBS : Transcription factor binding site TME : Tumor microenvironment