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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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@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>},
  articleno    = {1749},
  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},
  volume       = {10},
  year         = {2019},
}