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, Alvis Brazma and Chad J. Creighton ()
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Yiqun Zhang: Baylor College of Medicine
Fengju Chen: Baylor College of Medicine
Nuno A. Fonseca: European Bioinformatics Institute, (EMBL-EBI)
Yao He: Peking University
Masashi Fujita: RIKEN Center for Integrative Medical Sciences
Hidewaki Nakagawa: RIKEN Center for Integrative Medical Sciences
Zemin Zhang: Peking University
Alvis Brazma: European Bioinformatics Institute, (EMBL-EBI)
Chad J. Creighton: Baylor College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13885-w

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