CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells

Rene Opavsky, Shu Huei Wang, Prashant Trikha, Aparna Raval, Yuan Huang, Yue Zhong Wu, Benjamin Rodriguez, Benjamin Keller, Sandya Liyanarachchi, Guo Wei, Ramana V. Davuluri, Michael Weinstein, Dean Felsher, Michael Ostrowski, Gustavo Leone, Christoph Plass

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology.

Original languageEnglish (US)
Pages (from-to)1757-1769
Number of pages13
JournalPLoS genetics
Volume3
Issue number9
DOIs
StatePublished - Sep 2007

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Opavsky, R., Wang, S. H., Trikha, P., Raval, A., Huang, Y., Wu, Y. Z., Rodriguez, B., Keller, B., Liyanarachchi, S., Wei, G., Davuluri, R. V., Weinstein, M., Felsher, D., Ostrowski, M., Leone, G., & Plass, C. (2007). CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells. PLoS genetics, 3(9), 1757-1769. https://doi.org/10.1371/journal.pgen.0030167