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

被引：176

作者：

Akdemir, Kadir C. ^{[1
]}

Le, Victoria T. ^{[2
]}

Chandran, Sahaana ^{[2
]}

Li, Yilong ^{[3
]}

Verhaak, Roel G. ^{[4
]}

Beroukhim, Rameen ^{[5
,6
,7
,8
]}

Campbell, Peter J. ^{[3
,9
]}

Chin, Lynda ^{[10
]}

Dixon, Jesse R. ^{[2
]}

Futreal, P. Andrew ^{[1
]}

Alvarez, Eva G. ^{[11
,12
,13
]}

Baez-Ortega, Adrian ^{[14
]}

Beroukhim, Rameen ^{[5
,6
,7
,8
]}

Boutros, Paul C. ^{[15
,16
,17
,18
]}

Bowtell, David D. L. ^{[19
,20
]}

Brors, Benedikt ^{[21
,22
,23
]}

Burns, Kathleen H. ^{[24
]}

Chan, Kin ^{[25
]}

Chen, Ken ^{[26
]}

Cortes-Ciriano, Isidro ^{[27
,28
,29
]}

Dueso-Barroso, Ana ^{[30
]}

Dunford, Andrew J. ^{[7
]}

Edwards, Paul A. ^{[31
,32
]}

Estivill, Xavier ^{[33
]}

Etemadmoghadam, Dariush ^{[19
,34
]}

Feuerbach, Lars ^{[21
]}

Fink, J. Lynn ^{[30
,35
]}

Frenkel-Morgenstern, Milana ^{[36
]}

Garsed, Dale W. ^{[19
,34
]}

Gerstein, Mark ^{[37
,38
,39
,40
]}

Gordenin, Dmitry A. ^{[41
]}

Haan, David ^{[42
]}

Haber, James E. ^{[43
]}

Hess, Julian M. ^{[14
,44
]}

Hutter, Barbara ^{[23
,45
,46
]}

Imielinski, Marcin ^{[47
,48
]}

Jones, David T. W. ^{[49
,50
]}

Ju, Young Seok ^{[3
,51
]}

Kazanov, Marat D. ^{[52
,53
,54
]}

Klimczak, Leszek J. ^{[55
]}

Koh, Youngil ^{[56
,57
]}

Korbel, Jan O. ^{[58
,59
]}

Kumar, Kiran ^{[7
]}

Lee, Eunjung Alice ^{[60
,61
]}

Lee, Jake June-Koo ^{[28
,62
]}

Lynch, Andy G. ^{[31
,32
,63
,64
]}

Macintyre, Geoff ^{[31
]}

Markowetz, Florian ^{[31
,32
]}

Martincorena, Inigo ^{[3
]}

Martinez-Fundichely, Alexander ^{[65
,66
,67
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] Jackson Lab Genom Med, Div Computat Biol, Farmington, CT USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Canc Biol, Cambridge, MA USA

[7] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[8] Harvard Med Sch, Boston, MA 02115 USA

[9] Univ Cambridge, Dept Haematol, Cambridge, England

[10] Univ Texas Houston, Inst Hlth Transformat, Houston, TX USA

[11] Univ Santiago de Compostela, Dept Zool Genet & Phys Anthropol, Santiago De Compostela, Spain

[12] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Santiago De Compostela, Spain

[13] Univ Vigo, Biomed Res Ctr CINBIO, Vigo, Spain

[14] Univ Cambridge, Dept Vet Med, Transmissible Canc Grp, Cambridge, England

[15] Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada

[16] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[17] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada

[18] Univ Calif Los Angeles, Los Angeles, CA USA

[19] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[20] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[21] German Canc Res Ctr, Div Appl Bioinformat, Heidelberg, Germany

[22] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[23] Natl Ctr Tumor Dis NCT Heidelberg, Heidelberg, Germany

[24] Johns Hopkins Sch Med, Baltimore, MD USA

[25] Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada

[26] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[27] Univ Cambridge, Dept Chem, Ctr Mol Sci Informat, Cambridge, England

[28] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[29] Harvard Med Sch, Ludwig Ctr, Boston, MA 02115 USA

[30] BSC, Barcelona, Spain

[31] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[32] Univ Cambridge, Cambridge, England

[33] Sidra Med, Doha, Qatar

[34] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[35] Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia

[36] Bar Ilan Univ, Azrieli Fac Med, Safed, Israel

[37] Princeton Univ, Dept Comp Sci, Princeton, NJ 08544 USA

[38] Yale Univ, Dept Comp Sci, POB 2158, New Haven, CT 06520 USA

[39] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA

[40] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA

[41] NIEHS, Genome Integr & Struct Biol Lab, Durham, NC USA

[42] Univ Calif Santa Cruz, Biomol Engn Dept, Santa Cruz, CA 95064 USA

[43] Brandeis Univ, Waltham, MA USA

[44] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA

[45] German Canc Consortium DKTK, Heidelberg, Germany

[46] German Canc Res Ctr, Heidelberg Ctr Personalized Oncol DKFZ HIPO, Heidelberg, Germany

[47] New York Genome Ctr, New York, NY USA

[48] Weill Cornell Med, New York, NY USA

[49] Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany

[50] German Canc Res Ctr, Pediat Glioma Res Grp, Heidelberg, Germany

来源：

NATURE GENETICS | 2020年 / 52卷 / 03期

关键词：

INSULATED NEIGHBORHOODS; REVEALS; MAP; ORGANIZATION; ACTIVATION; EVOLUTION; TOPOLOGY;

D O I：

10.1038/s41588-019-0564-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

引用

页码：294 / +

页数：32

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