Abstract
BACKGROUND: Disruption of DNA methylation (DNAm) is one of the key signatures of cancer, however, detailed mechanisms that alter the DNA methylome in cancer remain to be elucidated. METHODS: Here we present a novel integrative analysis framework, called MeLncTRN (Methylation mediated LncRNA Transcriptional Regulatory Network), that integrates genome-wide transcriptome, DNA methylome and copy number variation profiles, to systematically identify the epigenetically-driven lncRNA-gene regulation circuits across 18 cancer types. FINDING: We show that a significant fraction of the aberrant DNAm and gene expression landscape in cancer is associated with long noncoding RNAs (lncRNAs). We reveal distinct types of regulation between lncRNA modulators and target genes that are operative in either only specific cancers or across cancers. Functional studies identified a common theme of cancer hallmarks that lncRNA modulators may participate in. The coupled lncRNA gene interactions via DNAm also serve as markers for classifications of cancer subtypes with different prognoses. INTERPRETATION: Our study reveals a vital layer of DNAm and associated expression regulation for many cancer-related genes and we also provide a valuable database resource for interrogating epigenetically mediated lncRNA-gene interactions in cancer. FUNDING: National Natural Science Foundation of China [91959106, 31871255].