Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Mol Cell. 2020 Mar 19;77(6):1307-1321.e10. doi: 10.1016/j.molcel.2019.12.027. Epub 2020 Jan 17.

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.

Keywords: ActiveDriverWGS; PCAWG; cancer genomics; driver mutations; epigenetics; gene regulation; non-coding genome; pan-cancer; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Cell Proliferation
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Computational Biology / methods
  • DNA Mutational Analysis
  • Gene Regulatory Networks*
  • Genome, Human
  • HEK293 Cells
  • Humans
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Regulatory Sequences, Nucleic Acid*

Substances

  • Biomarkers, Tumor
  • Chromatin

Grant support