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