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

Arie B. Brinkman; Serena Nik-Zainal; Femke Simmer; F. Germán Rodríguez-González; Marcel Smid; Ludmil B. Alexandrov; Adam Butler; Sancha Martin; Helen Davies; Dominik Glodzik; Xueqing Zou; Manasa Ramakrishna; Johan Staaf; Markus Ringnér; Anieta Sieuwerts; Anthony Ferrari; Sandro Morganella; Thomas Fleischer; Vessela Kristensen; Marta Gut; Marc J. van de Vijver; Anne Lise Børresen-Dale; Andrea L. Richardson; Gilles Thomas; Ivo G. Gut; John W.M. Martens; John A. Foekens; Michael R. Stratton; Hendrik G. Stunnenberg

doi:10.1038/s41467-019-09828-0

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

Arie B. Brinkman, Serena Nik-Zainal, Femke Simmer, F. Germán Rodríguez-González, Marcel Smid, Ludmil B. Alexandrov, Adam Butler, Sancha Martin, Helen Davies, Dominik Glodzik, Xueqing Zou, Manasa Ramakrishna, Johan Staaf, Markus Ringnér, Anieta Sieuwerts, Anthony Ferrari, Sandro Morganella, Thomas Fleischer, Vessela Kristensen, Marta GutMarc J. van de Vijver, Anne Lise Børresen-Dale, Andrea L. Richardson, Gilles Thomas, Ivo G. Gut, John W.M. Martens, John A. Foekens, Michael R. Stratton, Hendrik G. Stunnenberg

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

39 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Artikelnummer	1749
Tijdschrift	Nature Communications
Volume	10
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41467-019-09828-0
Status	Gepubliceerd - 1 dec. 2019
Extern gepubliceerd	Ja

Toegang tot document

10.1038/s41467-019-09828-0

Citeer dit

Brinkman, A. B., Nik-Zainal, S., Simmer, F., Rodríguez-González, F. G., Smid, M., Alexandrov, L. B., Butler, A., Martin, S., Davies, H., Glodzik, D., Zou, X., Ramakrishna, M., Staaf, J., Ringnér, M., Sieuwerts, A., Ferrari, A., Morganella, S., Fleischer, T., Kristensen, V., ... Stunnenberg, H. G. (2019). Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation. Nature Communications, 10(1), Artikel 1749. https://doi.org/10.1038/s41467-019-09828-0

@article{24c61544415348f7837361262d8c2461,

title = "Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation",

abstract = "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.",

author = "Brinkman, {Arie B.} and Serena Nik-Zainal and Femke Simmer and Rodr{\'i}guez-Gonz{\'a}lez, {F. Germ{\'a}n} and Marcel Smid and Alexandrov, {Ludmil B.} and Adam Butler and Sancha Martin and Helen Davies and Dominik Glodzik and Xueqing Zou and Manasa Ramakrishna and Johan Staaf and Markus Ringn{\'e}r and Anieta Sieuwerts and Anthony Ferrari and Sandro Morganella and Thomas Fleischer and Vessela Kristensen and Marta Gut and {van de Vijver}, {Marc J.} and B{\o}rresen-Dale, {Anne Lise} and Richardson, {Andrea L.} and Gilles Thomas and Gut, {Ivo G.} and Martens, {John W.M.} and Foekens, {John A.} and Stratton, {Michael R.} and Stunnenberg, {Hendrik G.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09828-0",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Brinkman, AB, Nik-Zainal, S, Simmer, F, Rodríguez-González, FG, Smid, M, Alexandrov, LB, Butler, A, Martin, S, Davies, H, Glodzik, D, Zou, X, Ramakrishna, M, Staaf, J, Ringnér, M, Sieuwerts, A, Ferrari, A, Morganella, S, Fleischer, T, Kristensen, V, Gut, M, van de Vijver, MJ, Børresen-Dale, AL, Richardson, AL, Thomas, G, Gut, IG, Martens, JWM, Foekens, JA, Stratton, MR & Stunnenberg, HG 2019, 'Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation', Nature Communications, vol. 10, nr. 1, 1749. https://doi.org/10.1038/s41467-019-09828-0

TY - JOUR

T1 - Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

AU - Brinkman, Arie B.

AU - Nik-Zainal, Serena

AU - Simmer, Femke

AU - Rodríguez-González, F. Germán

AU - Smid, Marcel

AU - Alexandrov, Ludmil B.

AU - Butler, Adam

AU - Martin, Sancha

AU - Davies, Helen

AU - Glodzik, Dominik

AU - Zou, Xueqing

AU - Ramakrishna, Manasa

AU - Staaf, Johan

AU - Ringnér, Markus

AU - Sieuwerts, Anieta

AU - Ferrari, Anthony

AU - Morganella, Sandro

AU - Fleischer, Thomas

AU - Kristensen, Vessela

AU - Gut, Marta

AU - van de Vijver, Marc J.

AU - Børresen-Dale, Anne Lise

AU - Richardson, Andrea L.

AU - Thomas, Gilles

AU - Gut, Ivo G.

AU - Martens, John W.M.

AU - Foekens, John A.

AU - Stratton, Michael R.

AU - Stunnenberg, Hendrik G.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064461295&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-09828-0

DO - 10.1038/s41467-019-09828-0

M3 - Article

C2 - 30988298

AN - SCOPUS:85064461295

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1749

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit