Pan-cancer noncoding genomic analysis identifies functional CDC20 promoter mutation hotspots

• Published in: iScience 2021-04, Vol.24 (4), p.102285-102285, Article 102285
• Main Authors: He, Zaoke, Wu, Tao, Wang, Shixiang, Zhang, Jing, Sun, Xiaoqin, Tao, Ziyu, Zhao, Xiangyu, Li, Huimin, Wu, Kai, Liu, Xue-Song
• Format: Article
• Language: English
• Subjects: Cancer; Cancer Systems Biology; Genetics; Genomics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102285

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 CDC20 gene. These CDC20 promoter hotspot mutations disrupt the binding of ELK4 transcription repressor, lead to the up-regulation of CDC20 transcription. Physiologically ELK4 binds to the unmutated hotspot sites and is involved in DNA damage-induced CDC20 transcriptional repression. Overall, our study not only identifies a detailed mechanism for CDC20 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. [Display omitted] •Pan-cancer noncoding analysis for mutations that influence protein factor binding•Recurrent mutations were identified in the promoter of CDC20 gene•Promoter hotspot mutations disrupt ELK4 binding, up-regulate CDC20 transcription•Promoter hotspot mutation site is involved in DNA damage-induced CDC20 repression Genetics; Genomics; Cancer Systems Biology; Cancer