生物
染色质
遗传学
基因
计算生物学
基因组
癌变
外显子组
索引
表观遗传学
外显子组测序
突变
基因型
单核苷酸多态性
作者
Helen He Zhu,Liis Uusküla-Reimand,Keren Isaev,Lina Wadi,Azad Alizada,Shimin Shuai,Vincent Huang,Dike Aduluso-Nwaobasi,Marta Paczkowska,Diala Abd-Rabbo,Oliver Ocsenas,Minggao Liang,John Thompson,Yao Li,Luyao Ruan,Michal Krassowski,Irakli Dzneladze,Jared T. Simpson,Mathieu Lupien,Lincoln Stein,Paul C. Boutros,Michael D. Wilson,Jüri Reimand
出处
期刊:Molecular Cell
[Elsevier]
日期:2020-03-01
卷期号:77 (6): 1307-1321.e10
被引量:54
标识
DOI:10.1016/j.molcel.2019.12.027
摘要
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.
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