Decoding DNA methylation and non-coding RNAs mediated regulatory landscape of breast tumor and adjacent normal tissues

Tumorigenesis not only involves perturbations of mRNAs but also microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and DNA methylation (DNAm). Additionally, the tumor-adjacent normal tissues (TANTs) that are used as controls in cancer studies are not completely normal and, if explored systematically, can help to understand tumorigenesis better. In this regard, expression and DNAm profiles of breast tumor tissues (viz., Luminal-A, Luminal-B, Her2+, Basal-like, and Normal-like) and TANTs were used to construct and analyze their integrative networks. These networks included regulations among genes, transcription factors, lncRNAs, and miRNAs, along with gene/lncRNA methylations. This followed the identification of candidate gene PCLAF having transitivity value one across all six tissue networks. Further, 503 common hubs (388 protein-coding, 100 miRNAs, and 15 lncRNAs), including seven methylated genes (SPI1, STAT5A, RORC, SPDEF, ELF5, HOXB2, and RUNX3), and 149 common bottlenecks (145 protein-coding, three miRNAs, and one lncRNA), including three methylated genes (SPI1, SPDEF, and RUNX3) and one methylated lncRNA (PART1), were identified. Moreover, 145 nodes, including three methylated genes (SPI1, SPDEF, and RUNX3) and three miRNAs (hsa-miR-34a, hsa-miR-149, and hsa-miR-141), were identified as both hubs and bottlenecks (HBs) across all six tissues. However, none of the lncRNAs were found HBs therein. Genes and lncRNAs with higher degrees, betweenness, eigenvector centrality, and pagerank were found more preferably methylated than others. Further, pathway analysis of hubs and bottlenecks across all six tissues revealed their significant involvement in the pathway of Transcriptional misregulation in cancer. Overall, these findings uncover new insights into the epigenetic mechanisms of tumorigenesis.