High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
(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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- author
- Zhang, Yiqun ; Chen, Fengju ; Fonseca, Nuno A ; He, Yao ; Fujita, Masashi ; Nakagawa, Hidewaki ; Zhang, Zemin ; Brazma, Alvis and Creighton, Chad J
- contributor
- Borg, Åke LU ; Ringnér, Markus LU and Staaf, Johan LU
- author collaboration
- organization
- publishing date
- 2020-02-05
- type
- Contribution to journal
- 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}}, }