| Literature DB >> 31954095 |
Helen Zhu1, Liis Uusküla-Reimand2, Keren Isaev1, Lina Wadi3, Azad Alizada4, Shimin Shuai5, Vincent Huang3, Dike Aduluso-Nwaobasi3, Marta Paczkowska3, Diala Abd-Rabbo3, Oliver Ocsenas1, Minggao Liang6, J Drew Thompson3, Yao Li3, Luyao Ruan3, Michal Krassowski3, Irakli Dzneladze3, Jared T Simpson7, Mathieu Lupien8, Lincoln D Stein5, Paul C Boutros9, Michael D Wilson6, Jüri Reimand10.
Abstract
A comprehensive catalog of cancer driver mutations is essential for understanding tumorigenesis and developing therapies. Exome-sequencing studies have mapped many protein-coding drivers, yet few non-coding drivers are known because genome-wide discovery is challenging. We developed a driver discovery method, ActiveDriverWGS, and analyzed 120,788 cis-regulatory modules (CRMs) across 1,844 whole tumor genomes from the ICGC-TCGA PCAWG project. We found 30 CRMs with enriched SNVs and indels (FDR < 0.05). These frequently mutated regulatory elements (FMREs) were ubiquitously active in human tissues, showed long-range chromatin interactions and mRNA abundance associations with target genes, and were enriched in motif-rewiring mutations and structural variants. Genomic deletion of one FMRE in human cells caused proliferative deficiencies and transcriptional deregulation of cancer genes CCNB1IP1, CDH1, and CDKN2B, validating observations in FMRE-mutated tumors. Pathway analysis revealed further sub-significant FMREs at cancer genes and processes, indicating an unexplored landscape of infrequent driver mutations in the non-coding genome.Entities:
Keywords: ActiveDriverWGS; PCAWG; cancer genomics; driver mutations; epigenetics; gene regulation; non-coding genome; pan-cancer; whole-genome sequencing
Year: 2020 PMID： 31954095 DOI： 10.1016/j.molcel.2019.12.027
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970