Melanoma-specific mutation hotspots in distal, non-coding, promoter-interacting regions implicate novel candidate driver genes

Abstract Investigations of the non-coding region are essential for uncovering the full spectrum of genetic drivers in melanoma. Here, we map distal, non-coding, promoter-interacting regulatory elements using Hi-C data from melanoma cells and integrating these with whole-genome sequence and gene expression data from the Pan Cancer Analysis of Whole Genomes. We identified eight recurrently mutated hotspots that are melanoma-specific, alter transcription factor binding motifs, and affect the expression of genes (e.g. HSPB7 , CLDN1, ADCY9 and FDXR ) previously implicated as tumor suppressors/oncogenes. Our study integrates multiple levels of biological data to uncover novel melanoma-specific non-coding candidate drivers beyond the well-characterized TERT promoter.