Pan-cancer noncoding genomic analysis identifies functional promoter mutation hotspots.

Noncoding DNA sequences occupy more than 98% of the human genome; however, few cancer noncoding drivers have been identified compared with cancer coding drivers, probably because cancer noncoding drivers have a distinct mutation pattern due to the distinct function of noncoding DNA. Here we performed pan-cancer whole genome mutation analysis to screen for functional noncoding mutations that influence protein factor binding. Recurrent mutations were identified in the promoter of gene. These promoter hotspot mutations disrupt the binding of ELK4 transcription repressor, lead to the up-regulation of transcription. Physiologically ELK4 binds to the unmutated hotspot sites and is involved in DNA damage-induced transcriptional repression. Overall, our study not only identifies a detailed mechanism for gene deregulation in human cancers but also finds functional noncoding genetic alterations, with implications for the further development of function-based noncoding driver discovery pipelines.