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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.