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High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

Author

Listed:
  • Yiqun Zhang

    (Baylor College of Medicine)

  • Fengju Chen

    (Baylor College of Medicine)

  • Nuno A. Fonseca

    (European Bioinformatics Institute, (EMBL-EBI)
    Universidade do Porto)

  • Yao He

    (Peking University
    Peking University)

  • Masashi Fujita

    (RIKEN Center for Integrative Medical Sciences)

  • Hidewaki Nakagawa

    (RIKEN Center for Integrative Medical Sciences)

  • Zemin Zhang

    (Peking University
    Peking University)

  • Alvis Brazma

    (European Bioinformatics Institute, (EMBL-EBI))

  • Chad J. Creighton

    (Baylor College of Medicine
    The University of Texas MD Anderson Cancer Center
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.

Suggested Citation

  • Yiqun Zhang & Fengju Chen & Nuno A. Fonseca & Yao He & Masashi Fujita & Hidewaki Nakagawa & Zemin Zhang & Alvis Brazma & Chad J. Creighton, 2020. "High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13885-w
    DOI: 10.1038/s41467-019-13885-w
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    Cited by:

    1. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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