Journal
MOLECULAR CELL
Volume 77, Issue 6, Pages 1307-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.12.027
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Funding
- Canadian Institutes of Health Research (CIHR)
- Ontario Institute for Cancer Research (OICR)
- Cancer Research Society (CRS) [21089, 21428, 21311]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2016-06485]
- OICR Brain Tumor Translational Research Initiative
- Isaiah 40:31 Memorial Fund [21089, 21428, 21311]
- OICR Biostatistics Training Initiative student fellowships
- CIHR Canadian Graduate Scholarship
- MBP Excellence Award
- The Estonian Research Council fellowship [PUTJD145]
- CIHR New Investigator Award
- Early Researcher Award from the Ontario Ministry of Research and Innovation
- Tier 2 Canada Research Chair from CIHR
- NSERC [RGPIN-2019-07041]
- OICR by the Government of Ontario
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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 CCNB11P1, 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.
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