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

Brinkman, Arie B. ; Nik-Zainal, Serena ; Simmer, Femke ; Rodríguez-González, F. Germán ; Smid, Marcel ; Alexandrov, Ludmil B. ; Butler, Adam ; Martin, Sancha ; Davies, Helen and Glodzik, Dominik LU , et al. (2019) In Nature Communications 10(1).
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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
10
issue
1
article number
1749
publisher
Nature Publishing Group
external identifiers
  • scopus:85064461295
  • pmid:30988298
  • pmid:30988298
ISSN
2041-1723
DOI
10.1038/s41467-019-09828-0
language
English
LU publication?
yes
id
f935f60b-9c89-4c9b-aefb-689523eabc54
date added to LUP
2019-04-30 14:55:54
date last changed
2024-04-30 05:27:15
@article{f935f60b-9c89-4c9b-aefb-689523eabc54,
  abstract     = {{<p>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.</p>}},
  author       = {{Brinkman, Arie B. and Nik-Zainal, Serena and Simmer, Femke and Rodríguez-González, F. Germán and Smid, Marcel and Alexandrov, Ludmil B. and Butler, Adam and Martin, Sancha and Davies, Helen and Glodzik, Dominik and Zou, Xueqing and Ramakrishna, Manasa and Staaf, Johan and Ringnér, Markus and Sieuwerts, Anieta and Ferrari, Anthony and Morganella, Sandro and Fleischer, Thomas and Kristensen, Vessela and Gut, Marta and van de Vijver, Marc J. and Børresen-Dale, Anne Lise and Richardson, Andrea L. and Thomas, Gilles and Gut, Ivo G. and Martens, John W.M. and Foekens, John A. and Stratton, Michael R. and Stunnenberg, Hendrik G.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-09828-0}},
  doi          = {{10.1038/s41467-019-09828-0}},
  volume       = {{10}},
  year         = {{2019}},
}