Integration of genetic and epigenetic alterations with tissue-specific network reveals regulatory drivers of prostate cancer

<p>We report a novel computational method, RegNetDriver, to identify regulatory drivers of tumorigenesis using combined effects of coding and non-coding single nucleotide variants, structural variants (SVs) and DNA methylation changes in the DNase I hypersensitivity based regulatory network. Integration of whole-genome sequencing, RNA-Seq and methylation data from 521 prostate tumor samples revealed a stronger regulatory impact of SVs, as they effect more transcription factor (TF) hubs in the tissue-specific network. Moreover, a crosstalk between TF hub expression modulated by SVs and methylation levels likely leads to differential expression of target genes. Using RegNetDriver, we report known TFs (ERG and P53) and nominate novel TFs supported by functional validation (ERF, CREB3L1 and POU2F2) as prostate regulatory drivers.