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Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks
- Zhu, Helen, Uusküla-Reimand, Liis, Isaev, Keren, Wadi, Lina, Alizada, Azad, Shuai, Shimin, Huang, Vincent, Aduluso-Nwaobasi, Dike, Paczkowska, Marta, Abd-Rabbo, Diala, Ocsenas, Oliver, Liang, Minggao, Thompson, J. Drew, Li, Yao, Ruan, Luyao, Krassowski, Michal, Dzneladze, Irakli, Simpson, Jared T., Lupien, Mathieu, Stein, Lincoln D., Boutros, Paul C., Wilson, Michael D., Reimand, Jüri
- Molecular cell 2019
- carcinogenesis, chromatin, genes, humans, messenger RNA, neoplasms, regulatory sequences, sequence analysis, sequence deletion, transcription (genetics)
- 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.