Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks.,Molecular Cell

当前位置： X-MOL 学术 › Mol. Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.molcel.2019.12.027
Helen Zhu ₁ , Liis Uusküla-Reimand ₂ , Keren Isaev ₁ , Lina Wadi ₃ , Azad Alizada ₄ , Shimin Shuai ₅ , Vincent Huang ₃ , Dike Aduluso-Nwaobasi ₃ , Marta Paczkowska ₃ , Diala Abd-Rabbo ₃ , Oliver Ocsenas ₁ , Minggao Liang ₆ , J Drew Thompson ₃ , Yao Li ₃ , Luyao Ruan ₃ , Michal Krassowski ₃ , Irakli Dzneladze ₃ , Jared T Simpson ₇ , Mathieu Lupien ₈ , Lincoln D Stein ₅ , Paul C Boutros ₉ , Michael D Wilson ₆ , Jüri Reimand ₁

Affiliation

Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street Suite 15-701, Toronto, ON M5G 1L7, Canada.
Program in Genetics and Genome Biology, SickKids Research Institute, Peter Gilgan Centre for Research and Learning (PGCRL), 686 Bay Street, Toronto, ON M5G 0A4, Canada; Division of Gene Technology, Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada.
Program in Genetics and Genome Biology, SickKids Research Institute, Peter Gilgan Centre for Research and Learning (PGCRL), 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Program in Genetics and Genome Biology, SickKids Research Institute, Peter Gilgan Centre for Research and Learning (PGCRL), 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada; Department of Computer Science, University of Toronto, 214 College Street, Toronto, ON M5T 3A1, Canada.
Department of Medical Biophysics, University of Toronto, 101 College Street Suite 15-701, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, 101 College Street, Toronto, ON M5G 0A3, Canada.
Department of Medical Biophysics, University of Toronto, 101 College Street Suite 15-701, Toronto, ON M5G 1L7, Canada; Department of Human Genetics, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; Department of Urology, University of California Los Angeles, 200 Medical Plaza Driveway #140, Los Angeles, CA 90024, USA; Institute of Precision Health, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024, USA; Jonsson Comprehensive Cancer Centre, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024, USA.

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.

中文翻译：

远距调节元件和远程染色质相互作用网络中的候选癌症驱动突变。

全面的癌症驱动程序突变目录对于理解肿瘤发生和发展疗法至关重要。外显子组测序研究已经绘制了许多蛋白质编码驱动程序，但由于全基因组发现具有挑战性，因此很少有人知道非编码驱动程序。我们开发了一种驱动程序发现方法ActiveDriverWGS，并通过ICGC-TCGA PCAWG项目分析了1,844个完整肿瘤基因组中的120,788个顺式调控模块（CRM）。我们发现了30个具有丰富SNV和插入缺失的CRM（FDR <0.05）。这些经常突变的调控元件（FMRE）在人体组织中普遍存在，表现出与目标基因的长距离染色质相互作用和mRNA丰度关联，并且富含基序改变突变和结构变异。人类细胞中一种FMRE的基因组缺失导致癌症基因CCNB1IP1，CDH1和CDKN2B的增殖缺陷和转录失调，验证了FMRE突变肿瘤中的观察结果。途径分析显示，在癌基因和过程中还有进一步的亚显着FMRE，表明非编码基因组中罕见的驱动子突变的未探究态势。

更新日期：2020-01-21

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11