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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

Akdemir, Kadir C ; Le, Victoria T ; Chandran, Sahaana ; Li, Yilong ; Verhaak, Roel G ; Beroukhim, Rameen ; Campbell, Peter J ; Chin, Lynda ; Dixon, Jesse R and Futreal, P Andrew (2020) In Nature Genetics 52(3). p.294-305
Abstract

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed... (More)

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.

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publication status
published
subject
keywords
Chromatin/genetics, Gene Expression Regulation, Neoplastic, Gene Rearrangement/genetics, Genome, Human/genetics, Genomic Structural Variation, Humans, Neoplasms/genetics
in
Nature Genetics
volume
52
issue
3
pages
294 - 305
publisher
Nature Publishing Group
external identifiers
  • scopus:85079073876
  • pmid:32024999
ISSN
1546-1718
DOI
10.1038/s41588-019-0564-y
language
English
LU publication?
yes
id
1228fbf0-3db4-4126-a102-77440ce7e8cd
date added to LUP
2023-03-29 17:31:34
date last changed
2024-04-18 20:30:19
@article{1228fbf0-3db4-4126-a102-77440ce7e8cd,
  abstract     = {{<p>Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.</p>}},
  author       = {{Akdemir, Kadir C and Le, Victoria T and Chandran, Sahaana and Li, Yilong and Verhaak, Roel G and Beroukhim, Rameen and Campbell, Peter J and Chin, Lynda and Dixon, Jesse R and Futreal, P Andrew}},
  issn         = {{1546-1718}},
  keywords     = {{Chromatin/genetics; Gene Expression Regulation, Neoplastic; Gene Rearrangement/genetics; Genome, Human/genetics; Genomic Structural Variation; Humans; Neoplasms/genetics}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{294--305}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer}},
  url          = {{http://dx.doi.org/10.1038/s41588-019-0564-y}},
  doi          = {{10.1038/s41588-019-0564-y}},
  volume       = {{52}},
  year         = {{2020}},
}