Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

被引：40

作者：

Brinkman, Arie B. ^{[1
]}

Nik-Zainal, Serena ^{[2
,3
]}

Simmer, Femke ^{[1
,18
]}

Rodriguez-Gonzalez, F. German ^{[4
,5
]}

Smid, Marcel ^{[4
,5
]}

Alexandrov, Ludmil B. ^{[2
,6
,7
]}

Butler, Adam ^{[2
]}

Martink, Sancha ^{[2
]}

Davies, Helen ^{[2
]}

Glodzik, Dominik ^{[2
]}

Zou, Xueqing ^{[2
]}

Ramakrishna, Manasa ^{[2
]}

Staaf, Johan ^{[8
]}

Ringrier, Markus ^{[8
]}

Sieuwerts, Anieta ^{[4
,5
]}

Ferrari, Anthony ^{[9
]}

Morganella, Sandro ^{[10
]}

Fleischer, Thomas ^{[11
]}

Kristensen, Vessela ^{[11
,12
,13
]}

Gut, Marta ^{[14
]}

van de Vijver, Marc J. ^{[15
]}

Borresen-Dale, Anne-Lise ^{[11
,12
]}

Richardson, Andrea L. ^{[16
,17
]}

Thomas, Gilles ^{[9
]}

Gut, Ivo G. ^{[14
]}

Martens, John W. M. ^{[4
,5
]}

Foekens, John A. ^{[4
,5
]}

Stratton, Michael R. ^{[2
]}

Stunnenberg, Hendrik G. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Fac Sci, Dept Mol Biol, POB 9101, NL-6500 HB Nijmegen, Netherlands

[2] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[3] Univ Cambridge, Acad Dept Med Genet, Cambridge CB2 0QQ, England

[4] Erasmus Univ, Erasmus MC Canc Inst, Med Ctr, NL-3015 GD Rotterdam, Netherlands

[5] Erasmus Univ, Canc Genom Netherlands, Dept Med Oncol, Med Ctr, NL-3015 GD Rotterdam, Netherlands

[6] Los Alamos Natl Lab, Theoret Biol & Biophys T6, Los Alamos, NM 87545 USA

[7] Los Alamos Natl Lab, Ctr Nonlinear Studies, Los Alamos, NM 87545 USA

[8] Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden

[9] Ctr Leon Berard, Synergie Lyon Canc, 28 Rue Laennec, Lyon 08, France

[10] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England

[11] Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway

[12] Univ Oslo, KG Jebsen Ctr Breast Canc Res, Inst Clin Med, N-0316 Oslo, Norway

[13] Akershus Univ Hosp, Dept Clin Mol Biol & Lab Sci EpiGen, Div Med, N-1478 Lorenskog, Norway

[14] Parc Cient Barcelona, CNAG, Barcelona 08028, Spain

[15] Acad Med Ctr, Dept Pathol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[16] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[17] Dana Farber Canc Inst, Boston, MA 02215 USA

[18] Radboud Univ Nijmegen, Dept Pathol, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国惠康基金; 欧盟第七框架计划;

关键词：

GENOMIC CHARACTERIZATION; CHROMATIN ORGANIZATION; DNA METHYLOME; CHROMOSOME; LANDSCAPE; MUTATION; SUBTYPES; PRINCIPLES; TUMORS; GENES;

D O I：

10.1038/s41467-019-09828-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.

引用

页数：10

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