Journal Article

DKFZ-2021-02564

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

Zhang, Y. ; Chen, F. ; Fonseca, N. A. ; He, Y. ; Fujita, M. ; Nakagawa, H. ; Zhang, Z. ; Brazma, A. ; PCAWGTranscriptomeWorkingGroup ; PCAWGStructuralVariationWorkingGroup ; Creighton, C. J. ; PCAWGConsortium

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-13885-w

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.

Keyword(s): DNA Methylation (MeSH) ; Databases, Genetic (MeSH) ; Enhancer Elements, Genetic (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Genes, Tumor Suppressor (MeSH) ; Genomic Structural Variation (MeSH) ; Humans (MeSH) ; Neoplasms: genetics (MeSH) ; Oncogenes (MeSH) ; Regulatory Sequences, Nucleic Acid (MeSH) ; Whole Genome Sequencing (MeSH)

Note: siehe Correction: DKFZ Autoren affiliiert im PCAWG Consortium: https://inrepo02.dkfz.de/record/212439 /https://doi.org/10.1038/s41467-022-32333-w

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Contributing Institute(s):

1. Theoretische Bioinformatik (B080)
2. Bioinformatik und Omics Data Analytics (B240)
3. Epigenomik (B370)
4. Angewandte Bioinformatik (B330)
5. DKTK HD zentral (HD01)
6. B060 Molekulare Genetik (B060)
7. Pädiatrische Gliomforschung (B360)
8. DKTK Koordinierungsstelle Berlin (BE01)
9. B062 Pädiatrische Neuroonkologie (B062)
10. B066 Chromatin-Netzwerke (B066)
11. B063 Krebsgenomforschung (B063)
12. Hochdurchsatz-Sequenzierung (W190)
13. B260 Bioinformatik der Genomik und Systemgenetik (B260)
14. Core Facility Omics IT (W610)
15. B087 Neuroblastom Genomik (B087)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2020

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