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

Zaoke He,Tao Wu,Shixiang Wang,Jing Zhang,Xiaoqin Sun,Ziyu Tao,Xiangyu Zhao,Huimin Li,Kai Wu,Xue-Song Liu

doi:10.1016/j.isci.2021.102285

Abstract

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 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.

Highlights

IntroductionSomatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of TERT promoter mutations (Bell et al, 2015; Horn et al, 2013; Huang et al, 2013)
Cancer develops primarily because of somatic alterations in the genomic DNA
Noncoding DNA sequences occupy more than 98% of the human genome; 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

Summary

Introduction

Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of TERT promoter mutations (Bell et al, 2015; Horn et al, 2013; Huang et al, 2013). Weinhold et al performed whole-genome sequences (WGS) analysis of 863 pan-cancer samples. Fredriksson et al analyzed 505 tumor genomes across 14 cancer types and identified no other frequent oncogenic promoter mutations beyond TERT. It was speculated that TERT promoter mutation is a rare exception in searching for cancer-driving noncoding genetic alterations (Fredriksson et al, 2014). A recent pan-cancer analysis of whole genomes (PCAWG) study with 2,658 WGS samples suggested that noncoding drivers are rare compared with protein-coding drivers (Rheinbay et al, 2020).

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