Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Helen Zhu¹, Liis Uusküla-Reimand², Keren Isaev¹, Lina Wadi³, Azad Alizada⁴, Shimin Shuai⁵, Vincent Huang³, Dike Aduluso-Nwaobasi³, Marta Paczkowska³, Diala Abd-Rabbo³, Oliver Ocsenas¹, Minggao Liang⁶, J Drew Thompson³, Yao Li³, Luyao Ruan³, Michal Krassowski³, Irakli Dzneladze³, Jared T Simpson⁷, Mathieu Lupien⁸, Lincoln D Stein⁵, Paul C Boutros⁹, Michael D Wilson⁶, Jüri Reimand¹⁰

Affiliations

¹ 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.
² 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.
³ Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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. Electronic address: juri.reimand@utoronto.ca.

PMID: 31954095
DOI: 10.1016/j.molcel.2019.12.027

Free article

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Helen Zhu et al. Mol Cell. 2020.

Free article

. 2020 Mar 19;77(6):1307-1321.e10.

doi: 10.1016/j.molcel.2019.12.027. Epub 2020 Jan 17.

Authors

Affiliations

¹ 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.
² 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.
³ Computational Biology Program, Ontario Institute for Cancer Research, 661 University Avenue Suite 510, Toronto, ON M5G 0A3, Canada.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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. Electronic address: juri.reimand@utoronto.ca.

PMID: 31954095
DOI: 10.1016/j.molcel.2019.12.027

Abstract

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.

Keywords: ActiveDriverWGS; PCAWG; cancer genomics; driver mutations; epigenetics; gene regulation; non-coding genome; pan-cancer; whole-genome sequencing.

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Conflict of interest statement

Declaration of Interest The authors declare no competing interests.

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Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Affiliations

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous