CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells.
CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells.
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DOI：
10.1371/journal.pgen.0030167
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发表时间：
2007-09
期刊：
影响因子：
4.5
通讯作者：
Plass C
中科院分区：
文献类型：
--
作者：
Opavsky R;Wang SH;Trikha P;Raval A;Huang Y;Wu YZ;Rodriguez B;Keller B;Liyanarachchi S;Wei G;Davuluri RV;Weinstein M;Felsher D;Ostrowski M;Leone G;Plass C
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. Genetic and epigenetic alterations of the genome are common features of cancers. The relationship between these two types of alterations, however, remains unclear. One type of epigenetic modification—DNA methylation in promoter sequences of genes—is of particular interest, since tumor cells have different patterns of promoter methylation than normal cells. Previous studies on human tumor samples have suggested a link between genetic alterations and the induction of aberrant DNA methylation; however, this link has been difficult to rigorously assess because of the incredible genetic heterogeneity found in human cancer. In this study, a mouse model of T cell lymphoma was used to explore the relationship between genetic and epigenetic modifications experienced by tumor cells. By introducing defined genetic changes into preneoplastic T cells of mice, such as the overexpression of the MYC oncogene and the ablation of tumor suppressor genes, we could carefully evaluate how these genetic changes impacted promoter methylation profiles during development of lymphomas in vivo. We found that the introduction of different genetic insults resulted in unique and diagnostic profiles of promoter methylation. Understanding how these methylation signatures contribute to tumor progression could eventually have diagnostic, prognostic, and therapeutic value for human cancers.
