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

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Lynch_2020_NC_High_VoR_CCBY.pdf (1.438Mb)
Date
05/02/2020
Author
Zhang, Yiqun
Chen, Fengju
Fonseca, Nuno A.
He, Yao
Fujita, Masashi
Nakagawa, Hidewaki
Zhang, Zemin
PCAWG Transcriptome Working Group
PCAWG Structural Variation Working Group
Creighton, Chad J.
PCAWG Consortium
Keywords
Cancer genomics
Gene expression
QH426 Genetics
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)
3rd-DAS
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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.
Citation
Zhang , Y , Chen , F , Fonseca , N A , He , Y , Fujita , M , Nakagawa , H , Zhang , Z , PCAWG Transcriptome Working Group , PCAWG Structural Variation Working Group , Creighton , C J & PCAWG Consortium 2020 , ' High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations ' , Nature Communications , vol. 11 , 736 . https://doi.org/10.1038/s41467-019-13885-w
Publication
Nature Communications
Status
Peer reviewed
DOI
https://doi.org/10.1038/s41467-019-13885-w
ISSN
2041-1723
Type
Journal article
Rights
Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Description
Funding: This work was supported in part by National Institutes of Health (NIH) grant P30CA125123 (C. Creighton) and Cancer Prevention and Research Institute of Texas (CPRIT) grant RP120713 C2 (C. Creighton).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/19680

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