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

Zhang, Yiqun ; Chen, Fengju ; Fonseca, Nuno A ; He, Yao ; Fujita, Masashi ; Nakagawa, Hidewaki ; Zhang, Zemin ; Brazma, Alvis and Creighton, Chad J (2020) In Nature Communications 11.
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,... (More)

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.

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type
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publication status
published
subject
keywords
DNA Methylation, Databases, Genetic, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genomic Structural Variation, Humans, Neoplasms/genetics, Oncogenes, Regulatory Sequences, Nucleic Acid, Whole Genome Sequencing
in
Nature Communications
volume
11
article number
736
pages
14 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:32024823
  • scopus:85079031729
ISSN
2041-1723
DOI
10.1038/s41467-019-13885-w
language
English
LU publication?
yes
id
8246d18f-bd2a-49bb-b898-c873c1c0d5e4
date added to LUP
2023-01-05 14:19:00
date last changed
2024-06-13 22:05:24
@article{8246d18f-bd2a-49bb-b898-c873c1c0d5e4,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Yiqun and Chen, Fengju and Fonseca, Nuno A and He, Yao and Fujita, Masashi and Nakagawa, Hidewaki and Zhang, Zemin and Brazma, Alvis and Creighton, Chad J}},
  issn         = {{2041-1723}},
  keywords     = {{DNA Methylation; Databases, Genetic; Enhancer Elements, Genetic; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genomic Structural Variation; Humans; Neoplasms/genetics; Oncogenes; Regulatory Sequences, Nucleic Acid; Whole Genome Sequencing}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-13885-w}},
  doi          = {{10.1038/s41467-019-13885-w}},
  volume       = {{11}},
  year         = {{2020}},
}