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

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

Authors:	Zhang, Y.; Chen, F.; Fonseca, N. A.; He, Y.; Fujita, M.; Nakagawa, H.; Zhang, Z.; Brazma, A.; PCAWG Transcriptome Working Group; PCAWG Structural Variation Working Group; & PCAWG Consortium
Contributors:	Abeshouse, A.; Al-Ahmadie, H.; Armenia, J.; Chen, H. W.; Davidson, N. R.; Gao, J.; Ghossein, R.; Giri, D. D.; Gundem, G.; Heins, Z.; Huse, J.; Iacobuzio-Donahue, C. A.; Kahles, A.; King, T. A.; Kundra, R.; Lehmann, K. V.; Levine, D. A.; Liu, E. M.; Ochoa, A.; Pastore, A.; Rätsch, G.; Reis-Filho, J.; Reuter, V.; Roehrl, M. H. A.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Senbabaoglu, Y.; Singer, S.; Socci, N. D.; Stark, S. G.; Vázquez-García, I.; Yellapantula, V. D.; Zhang, H.
Article 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 ~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. © 2020, The Author(s).
Keywords:	methylation; promoter region; genetics; genetic analysis; neoplasm; neoplasms; melanoma; gene amplification; gene expression; epidermal growth factor receptor 2; genetic association; gene frequency; genetic variation; gene function; dna methylation; oncogenes; sarcoma; rna; gene expression regulation; genome analysis; oncogene; tumor suppressor gene; gene expression regulation, neoplastic; dna; gene rearrangement; gene repression; telomerase reverse transcriptase; stomach cancer; gene control; liver cancer; genome; upregulation; kidney cancer; tumor gene; genes, tumor suppressor; somatomedin b; cyclin dependent kinase 4; protein mdm2; bile duct cancer; genetic database; databases, genetic; programmed death 1 ligand 1; programmed death 1 receptor; enhancer region; enhancer elements, genetic; regulatory sequences, nucleic acid; regulatory sequence; erbb2 gene; cdk4 gene; mdm2 gene; genomic structural variation; tert gene; cancer; humans; human; article; whole genome sequencing; rna sequencing; programmed death 1 ligand 2; pdl1 gene; cd274 gene; igf2 gene; pd1 gene; pdcd1lg2 gene
Journal Title:	Nature Communications
Volume:	11
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2020-02-05
Start Page:	736
Language:	English
DOI:	10.1038/s41467-019-13885-w
PUBMED:	32024823
PROVIDER:	scopus
PMCID:	PMC7002524
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85079031729&doi=10.1038%2fs41467-019-13885-w&partnerID=40&md5=fec2a9309fe4d5369d6e863931743936
Notes:	Article -- Erratum issued, see DOI: 10.1038/s41467-022-32333-w -- Export Date: 13 January 2023 -- Source: Scopus