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PMID: 21324880 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors.

Genome research ·Vol. 21 ·No. 4 ·2011-04-00 ·Pages 515-24

Feber A, Wilson GA, Zhang L, Presneau N, Idowu B, Down TA, Rakyan VK, Noon LA, Lloyd AC, Stupka E, Schiza V, Teschendorff AE, Schroth GP, Flanagan A, Beck S

Abstract

Aberrant DNA methylation (DNAm) was first linked to cancer over 25 yr ago. Since then, many studies have associated hypermethylation of tumor suppressor genes and hypomethylation of oncogenes to the tumorigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. By using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumors (MPNSTs), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. In contrast to what has been reported for other tumor types, no significant global hypomethylation was observed in MPNSTs using methylome analysis by MeDIP-seq. However, a highly significant (P < 10(-100)) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNSTs. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARLα) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P < 10(-60)), non-CGI-associated promoters (P < 10(-4)) and hypomethylated cDMRs in SINE repeats (P < 10(-100)) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyze cancer methylomes.

MeSH Terms
Cluster Analysis CpG Islands/genetics DNA Methylation/genetics Epigenomics Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Minisatellite Repeats/genetics Nerve Sheath Neoplasms/genetics Oligonucleotide Array Sequence Analysis/methods
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Feber Andrew
Medical Genomics, UCL Cancer Institute, University College London, London, United Kingdom. [email protected]
Wilson Gareth A
Zhang Lu
Presneau Nadege
Idowu Bernadine
Down Thomas A
Rakyan Vardhman K
Noon Luke A
Lloyd Alison C
Stupka Elia
Schiza Vassia
Teschendorff Andrew E
Schroth Gary P
Flanagan Adrienne
Beck Stephan
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.109678.110
Email
[email protected]
Published
2011-04-00
Epub
2011-00-01
Pages
515-24
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC3065699
Subset
IM
Grants
Cancer Research UK · 11244 · United Kingdom
Wellcome Trust · 084071 · United Kingdom
Databases
GEO
GSE21714
External Links
PubMed source DOI: 10.1101/gr.109678.110 PMC Full Text View journal details
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