A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases

Yiqun Zhang; Lixing Yang; Melanie Kucherlapati; Fengju Chen; Angela Hadjipanayis; Angeliki Pantazi; Christopher A. Bristow; Eunjung A. Lee; Harshad S. Mahadeshwar; Jiabin Tang; Jianhua Zhang; Sahil Seth; Semin Lee; Xiaojia Ren; Xingzhi Song; Huandong Sun; Jonathan Seidman; Lovelace J. Luquette; Ruibin Xi; Lynda Chin; Alexei Protopopov; Wei Li; Peter J. Park; Raju Kucherlapati; Chad J. Creighton

Cell Reports (Jul 2018)

A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases

Yiqun Zhang,
Lixing Yang,
Melanie Kucherlapati,
Fengju Chen,
Angela Hadjipanayis,
Angeliki Pantazi,
Christopher A. Bristow,
Eunjung A. Lee,
Harshad S. Mahadeshwar,
Jiabin Tang,
Jianhua Zhang,
Sahil Seth,
Semin Lee,
Xiaojia Ren,
Xingzhi Song,
Huandong Sun,
Jonathan Seidman,
Lovelace J. Luquette,
Ruibin Xi,
Lynda Chin,
Alexei Protopopov,
Wei Li,
Peter J. Park,
Raju Kucherlapati,
Chad J. Creighton

Affiliations

Yiqun Zhang: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
Lixing Yang: Ben May Department for Cancer Research, Department of Human Genetics, Institute for Genomics and Systems Biology, and Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA
Melanie Kucherlapati: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
Fengju Chen: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
Angela Hadjipanayis: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
Angeliki Pantazi: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; KEW Inc, Cambridge, MA 02139, USA
Christopher A. Bristow: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Eunjung A. Lee: Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Harshad S. Mahadeshwar: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jiabin Tang: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jianhua Zhang: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Sahil Seth: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Semin Lee: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
Xiaojia Ren: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; KEW Inc, Cambridge, MA 02139, USA
Xingzhi Song: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Huandong Sun: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jonathan Seidman: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Lovelace J. Luquette: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
Ruibin Xi: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
Lynda Chin: Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
Alexei Protopopov: KEW Inc, Cambridge, MA 02139, USA; Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Wei Li: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Peter J. Park: Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
Raju Kucherlapati: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
Chad J. Creighton: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 2
pp. 515 – 527

Abstract

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Summary: A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes—including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)—show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA. : Zhang et al. analyzed over 1,400 cancers by high- or low-pass whole-genome sequencing, focusing on patterns of structural variation. They saw a widespread impact of somatic structural variants on gene expression patterns, independent of copy-number alterations, involving key oncogenes and tumor suppressor genes. Keywords: cancer, structural variation, genomic rearrangement, whole genome sequencing, pan-cancer, TCGA

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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