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DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status.

Lauss, Martin LU ; Aine, Mattias LU ; Sjödahl, Gottfrid LU ; Veerla, Srinivas; Hultman Patschan, Oliver LU ; Gudjonsson, Sigurdur LU ; Chebil, Gunilla; Lövgren, Kristina LU ; Fernö, Mårten LU and Månsson, Wiking LU , et al. (2012) In Epigenetics 7(8). p.858-867
Abstract
We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes, and... (More)
We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes, and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC. (Less)
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Contribution to journal
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published
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Epigenetics
volume
7
issue
8
pages
858 - 867
publisher
Landes Bioscience
external identifiers
  • wos:000307239400008
  • pmid:22705924
  • scopus:84864701954
ISSN
1559-2294
DOI
10.4161/epi.20837
language
English
LU publication?
yes
id
70222596-55ed-467d-b99e-f7ea25dfa060 (old id 2859313)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22705924?dopt=Abstract
date added to LUP
2012-07-04 18:07:45
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2017-11-19 03:08:42
@article{70222596-55ed-467d-b99e-f7ea25dfa060,
  abstract     = {We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes, and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC.},
  author       = {Lauss, Martin and Aine, Mattias and Sjödahl, Gottfrid and Veerla, Srinivas and Hultman Patschan, Oliver and Gudjonsson, Sigurdur and Chebil, Gunilla and Lövgren, Kristina and Fernö, Mårten and Månsson, Wiking and Liedberg, Fredrik and Ringnér, Markus and Lindgren, David and Höglund, Mattias},
  issn         = {1559-2294},
  language     = {eng},
  number       = {8},
  pages        = {858--867},
  publisher    = {Landes Bioscience},
  series       = {Epigenetics},
  title        = {DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status.},
  url          = {http://dx.doi.org/10.4161/epi.20837},
  volume       = {7},
  year         = {2012},
}