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

doi:10.1016/j.celrep.2018.06.025

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

Cell Rep. 2018 Jul 10;24(2):515-527. doi: 10.1016/j.celrep.2018.06.025.

Authors

Yiqun Zhang¹, Lixing Yang², Melanie Kucherlapati³, Fengju Chen¹, Angela Hadjipanayis³, Angeliki Pantazi⁴, Christopher A Bristow⁵, Eunjung A Lee⁶, Harshad S Mahadeshwar⁵, Jiabin Tang⁵, Jianhua Zhang⁵, Sahil Seth⁵, Semin Lee⁷, Xiaojia Ren⁴, Xingzhi Song⁵, Huandong Sun⁵, Jonathan Seidman⁸, Lovelace J Luquette⁷, Ruibin Xi⁷, Lynda Chin⁹, Alexei Protopopov¹⁰, Wei Li¹¹, Peter J Park¹², Raju Kucherlapati³, Chad J Creighton¹³

Affiliations

¹ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
² 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.
³ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; KEW Inc, Cambridge, MA 02139, USA.
⁵ Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷ Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
¹³ 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. Electronic address: creighto@bcm.edu.

Abstract

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.

Keywords: TCGA; cancer; genomic rearrangement; pan-cancer; structural variation; whole genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Carcinogenesis / genetics
Carcinogenesis / pathology
DNA Copy Number Variations / genetics
Enhancer Elements, Genetic / genetics
Gene Expression Regulation, Neoplastic*
Gene Rearrangement / genetics*
Genes, Neoplasm*
Genome, Human*
Humans
Neoplasms / genetics*

Abstract

Publication types

MeSH terms

Grants and funding