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

Yiqun Zhang; Fengju Chen; Nuno A. Fonseca; Yao He; Masashi Fujita; Hidewaki Nakagawa; Zemin Zhang; Samirkumar B. Amin; Philip Awadalla; Peter J. Bailey; Alvis Brazma; Chad J. Creighton; PCAWG Transcriptome Working Group; PCAWG Structural Variation Working Group; PCAWG Consortium; Neil Merrett; et al.

doi:10.1038/s41467-019-13885-w

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

Yiqun Zhang
, Fengju Chen
, Nuno A. Fonseca
, Yao He
, Masashi Fujita
, Hidewaki Nakagawa
, Zemin Zhang
, Samirkumar B. Amin
, Philip Awadalla
, Peter J. Bailey
, Alvis Brazma
, Chad J. Creighton
, PCAWG Transcriptome Working Group
, PCAWG Structural Variation Working Group
, PCAWG Consortium
, Neil Merrett
, et al.

School of Medicine

Baylor College of Medicine
European Molecular Biology Laboratory
University of Porto
Peking University
RIKEN
University of Texas MD Anderson Cancer Center
Jackson Laboratory
Ontario Institute for Cancer Research
University of Toronto
University of Glasgow
University of Texas

Research output: Contribution to journal › Article › peer-review

65 Citations (Scopus)

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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. There is a Correction to the Article - https://doi.org/10.1038/s41467-022-32333-w

Original language	English
Article number	736
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13885-w
Publication status	Published - 1 Dec 2020

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Cite this

Zhang, Y., Chen, F., Fonseca, N. A., He, Y., Fujita, M., Nakagawa, H., Zhang, Z., Amin, S. B., Awadalla, P., Bailey, P. J., Brazma, A., Creighton, C. J., PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Merrett, N., & et al. (2020). High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. Nature Communications, 11(1), Article 736. https://doi.org/10.1038/s41467-019-13885-w

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

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 \textasciitilde{}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 \textasciitilde{}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. There is a Correction to the Article - https://doi.org/10.1038/s41467-022-32333-w",

author = "Yiqun Zhang and Fengju Chen and Fonseca, \{Nuno A.\} and Yao He and Masashi Fujita and Hidewaki Nakagawa and Zemin Zhang and Amin, \{Samirkumar B.\} and Philip Awadalla and Bailey, \{Peter J.\} and Alvis Brazma and Creighton, \{Chad J.\} and \{PCAWG Transcriptome Working Group\} and \{PCAWG Structural Variation Working Group\} and \{PCAWG Consortium\} and Neil Merrett and \{et al.\}",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13885-w",

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Zhang, Y, Chen, F, Fonseca, NA, He, Y, Fujita, M, Nakagawa, H, Zhang, Z, Amin, SB, Awadalla, P, Bailey, PJ, Brazma, A, Creighton, CJ, PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, , Merrett, N & et al. 2020, 'High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations', Nature Communications, vol. 11, no. 1, 736. https://doi.org/10.1038/s41467-019-13885-w

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AU - Zhang, Yiqun

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AU - Fonseca, Nuno A.

AU - He, Yao

AU - Fujita, Masashi

AU - Nakagawa, Hidewaki

AU - Zhang, Zemin

AU - Amin, Samirkumar B.

AU - Awadalla, Philip

AU - Bailey, Peter J.

AU - Brazma, Alvis

AU - Creighton, Chad J.

AU - PCAWG Transcriptome Working Group,

AU - PCAWG Structural Variation Working Group,

AU - PCAWG Consortium,

AU - Merrett, Neil

AU - et al.,

PY - 2020/12/1

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N2 - 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. There is a Correction to the Article - https://doi.org/10.1038/s41467-022-32333-w

AB - 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. There is a Correction to the Article - https://doi.org/10.1038/s41467-022-32333-w

UR - https://www.scopus.com/pages/publications/85079031729

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DO - 10.1038/s41467-019-13885-w

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AN - SCOPUS:85079031729

SN - 2041-1723

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IS - 1

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ER -

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

Abstract

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