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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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Author(s)

PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Yiqun Zhang, Fengju Chen, Nuno A. Fonseca, Yao He, Masashi Fujita, Hidewaki Nakagawa, Zemin Zhang, Alvis Brazma, Samirkumar B. Amin, Philip Awadalla, Peter J. Bailey, Alvis Brazma, Angela N. Brooks, Claudia Calabrese, Aurélien Chateigner, Isidro Cortés-Ciriano, Brian Craft & 33 more David Craft, Chad J. Creighton, Natalie R. Davidson, Deniz Demircioğlu, Serap Erkek, Nuno A. Fonseca, Milana Frenkel-Morgenstern, Mary J. Goldman, Liliana Greger, Jonathan Göke, Yao He, Katherine A. Hoadley, Yong Hou, Matthew R. Huska, Andre Kahles, Ekta Khurana, Helena Kilpinen, Jan O. Korbel, Fabien C. Lamaze, Kjong Van Lehmann, Chang Li, Siliang Li, Xiaobo Li, Xinyue Li, Dongbing Liu, Fenglin Liu, Xingmin Liu, Maximillian G. Marin, Julia Markowski, Matthew Meyerson, Tannistha Nandi, Morten Muhlig Nielsen, Andy G. Lynch

School/Research organisations

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.

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Original languageEnglish
Article number736
Number of pages14
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 5 Feb 2020

    Research areas

  • Cancer genomics, Gene expression

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