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

Kadir C. Akdemir; Victoria T. Le; Sahaana Chandran; Yilong Li; Roel G. Verhaak; Rameen Beroukhim; Peter J. Campbell; Lynda Chin; Jesse R. Dixon; P. Andrew Futreal; Kadir C. Akdemir; Eva G. Alvarez; Adrian Baez-Ortega; Paul C. Boutros; David D.L. Bowtell; Benedikt Brors; Kathleen H. Burns; Peter J. Campbell; Kin Chan; Ken Chen; Isidro Cortés-Ciriano; Ana Dueso-Barroso; Andrew J. Dunford; Paul A. Edwards; Xavier Estivill; Dariush Etemadmoghadam; Lars Feuerbach; J. Lynn Fink; Milana Frenkel-Morgenstern; Dale W. Garsed; Mark Gerstein; Dmitry A. Gordenin; David Haan; James E. Haber; Julian M. Hess; Barbara Hutter; Marcin Imielinski; David T.W. Jones; Young Seok Ju; Marat D. Kazanov; Leszek J. Klimczak; Youngil Koh; Jan O. Korbel; Kiran Kumar; Eunjung Alice Lee; Jake June Koo Lee; Yilong Li; Andy G. Lynch; Geoff Macintyre; Florian Markowetz; PCAWG Consortium; PCAWG-Structural Variation Working Group; David Townend

doi:10.1038/s41588-019-0564-y

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

Kadir C. Akdemir, Victoria T. Le, Sahaana Chandran, Yilong Li, Roel G. Verhaak, Rameen Beroukhim, Peter J. Campbell, Lynda Chin, Jesse R. Dixon, P. Andrew Futreal^*, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Paul C. Boutros, David D.L. Bowtell, Benedikt Brors, Kathleen H. Burns, Peter J. Campbell, Kin Chan, Ken ChenIsidro Cortés-Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Lars Feuerbach, J. Lynn Fink, Milana Frenkel-Morgenstern, Dale W. Garsed, Mark Gerstein, Dmitry A. Gordenin, David Haan, James E. Haber, Julian M. Hess, Barbara Hutter, Marcin Imielinski, David T.W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Jan O. Korbel, Kiran Kumar, Eunjung Alice Lee, Jake June Koo Lee, Yilong Li, Andy G. Lynch, Geoff Macintyre, Florian Markowetz, PCAWG Consortium, PCAWG-Structural Variation Working Group, David Townend

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	294-305
Number of pages	12
Journal	Nature Genetics
Volume	52
Issue number	3
DOIs	https://doi.org/10.1038/s41588-019-0564-y
Publication status	Published - 1 Mar 2020

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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., Akdemir, K. C., Alvarez, E. G., Baez-Ortega, A., Boutros, P. C., Bowtell, D. D. L., Brors, B., Burns, K. H., Campbell, P. J., Chan, K., ... Townend, D. (2020). Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nature Genetics, 52(3), 294-305. https://doi.org/10.1038/s41588-019-0564-y

@article{c76f312446fb447db1568afbe82bf9f8,

title = "Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer",

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.",

author = "Akdemir, {Kadir C.} and Le, {Victoria T.} and Sahaana Chandran and Yilong Li and Verhaak, {Roel G.} and Rameen Beroukhim and Campbell, {Peter J.} and Lynda Chin and Dixon, {Jesse R.} and Futreal, {P. Andrew} and Akdemir, {Kadir C.} and Alvarez, {Eva G.} and Adrian Baez-Ortega and Boutros, {Paul C.} and Bowtell, {David D.L.} and Benedikt Brors and Burns, {Kathleen H.} and Campbell, {Peter J.} and Kin Chan and Ken Chen and Isidro Cort{\'e}s-Ciriano and Ana Dueso-Barroso and Dunford, {Andrew J.} and Edwards, {Paul A.} and Xavier Estivill and Dariush Etemadmoghadam and Lars Feuerbach and Fink, {J. Lynn} and Milana Frenkel-Morgenstern and Garsed, {Dale W.} and Mark Gerstein and Gordenin, {Dmitry A.} and David Haan and Haber, {James E.} and Hess, {Julian M.} and Barbara Hutter and Marcin Imielinski and Jones, {David T.W.} and Ju, {Young Seok} and Kazanov, {Marat D.} and Klimczak, {Leszek J.} and Youngil Koh and Korbel, {Jan O.} and Kiran Kumar and Lee, {Eunjung Alice} and Lee, {Jake June Koo} and Yilong Li and Lynch, {Andy G.} and Geoff Macintyre and Florian Markowetz and {PCAWG Consortium} and {PCAWG-Structural Variation Working Group} and David Townend",

note = "Funding Information: 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{\textquoteright}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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41588-019-0564-y",

language = "English",

volume = "52",

pages = "294--305",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

Akdemir, KC, Le, VT, Chandran, S, Li, Y, Verhaak, RG, Beroukhim, R, Campbell, PJ, Chin, L, Dixon, JR, Futreal, PA, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Campbell, PJ, Chan, K, Chen, K, Cortés-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Lee, JJK, Li, Y, Lynch, AG, Macintyre, G, Markowetz, F, PCAWG Consortium, PCAWG-Structural Variation Working Group & Townend, D 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

TY - JOUR

T1 - Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

AU - Akdemir, Kadir C.

AU - Le, Victoria T.

AU - Chandran, Sahaana

AU - Li, Yilong

AU - Verhaak, Roel G.

AU - Beroukhim, Rameen

AU - Campbell, Peter J.

AU - Chin, Lynda

AU - Dixon, Jesse R.

AU - Futreal, P. Andrew

AU - Akdemir, Kadir C.

AU - Alvarez, Eva G.

AU - Baez-Ortega, Adrian

AU - Boutros, Paul C.

AU - Bowtell, David D.L.

AU - Brors, Benedikt

AU - Burns, Kathleen H.

AU - Campbell, Peter J.

AU - Chan, Kin

AU - Chen, Ken

AU - Cortés-Ciriano, Isidro

AU - Dueso-Barroso, Ana

AU - Dunford, Andrew J.

AU - Edwards, Paul A.

AU - Estivill, Xavier

AU - Etemadmoghadam, Dariush

AU - Feuerbach, Lars

AU - Fink, J. Lynn

AU - Frenkel-Morgenstern, Milana

AU - Garsed, Dale W.

AU - Gerstein, Mark

AU - Gordenin, Dmitry A.

AU - Haan, David

AU - Haber, James E.

AU - Hess, Julian M.

AU - Hutter, Barbara

AU - Imielinski, Marcin

AU - Jones, David T.W.

AU - Ju, Young Seok

AU - Kazanov, Marat D.

AU - Klimczak, Leszek J.

AU - Koh, Youngil

AU - Korbel, Jan O.

AU - Kumar, Kiran

AU - Lee, Eunjung Alice

AU - Lee, Jake June Koo

AU - Li, Yilong

AU - Lynch, Andy G.

AU - Macintyre, Geoff

AU - Markowetz, Florian

AU - PCAWG Consortium

AU - PCAWG-Structural Variation Working Group

AU - Townend, David

N1 - Funding Information: 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. Publisher Copyright: © 2020, The Author(s).

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-019-0564-y

DO - 10.1038/s41588-019-0564-y

M3 - Article

SN - 1061-4036

VL - 52

SP - 294

EP - 305

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

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