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

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Lynch_2020_NatGen_Disruptionofchromatin_VoR_CCBY.pdf (15.80Mb)
Date
03/2020
Author
Akdemir, Kadir C.
Le, Victoria T.
Chandran, Sahaana
Li, Yilong
Verhaak, Roel G.
Beroukhim, Rameen
Campbell, Peter J.
Chin, Lynda
Dixon, Jesse R.
Futreal, P. Andrew
PCAWG Structural Variation Working Group
PCAWG Consortium
Keywords
Cancer
Data mining
Gene expression
QH301 Biology
QH426 Genetics
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Genetics
3rd-DAS
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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 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.
Citation
Akdemir , K C , Le , V T , Chandran , S , Li , Y , Verhaak , R G , Beroukhim , R , Campbell , P J , Chin , L , Dixon , J R , Futreal , P A , PCAWG Structural Variation Working Group & PCAWG Consortium 2020 , ' Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer ' , Nature Genetics , vol. 52 , no. 3 , pp. 294-305 . https://doi.org/10.1038/s41588-019-0564-y
Publication
Nature Genetics
Status
Peer reviewed
DOI
https://doi.org/10.1038/s41588-019-0564-y
ISSN
1061-4036
Type
Journal article
Rights
Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap-tation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statu-tory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Description
We thank the patients and their families for contributing to this study, S. Dent, Z. Coban Akdemir, E. Z. Keung, T. Gutschner, D. Spring, J. Korbel and J. Stuart for reading the manuscript, F. Scott, S. Amin, S. Seth, F. Barthel, T. Mang, X. Song and J. Zhang for discussions, all ICGC subgroup participants for generating readily accessible mutation calls and uniformly analyzed gene-expression datasets. This work was supported by a Cancer Prevention Research Institute of Texas award (R1205), the Welch Foundation’s Robert A. Welch Distinguished Chair Award (G-0040 to P.A.F.) and the Emerson Collective Cancer Research Fund (to K.C.A.). J.R.D. is supported by an NIH Director’s Early Independence Award (DP5OD023071). We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/19845

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