摘要：SummaryNoncoding 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 ofCDC20gene. TheseCDC20promoter hotspot mutations disrupt the binding of ELK4 transcription repressor, lead to the up-regulation ofCDC20transcription. Physiologically ELK4 binds to the unmutated hotspot sites and is involved in DNA damage-inducedCDC20transcriptional repression. Overall, our study not only identifies a detailed mechanism forCDC20gene deregulation in human cancers but also finds functional noncoding genetic alterations, with implications for the further development of function-based noncoding driver discovery pipelines.Graphical abstractDisplay OmittedHighlights•Pan-cancer noncoding analysis for mutations that influence protein factor binding•Recurrent mutations were identified in the promoter ofCDC20gene•Promoter hotspot mutations disrupt ELK4 binding, up-regulateCDC20transcription•Promoter hotspot mutation site is involved in DNA damage-inducedCDC20repressionGenetics; Genomics; Cancer Systems Biology; Cancer
