CpG Island Methylation in a Mouse Model of Lymphoma Is Driven by the Genetic Configuration of Tumor Cells

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.

CpG岛（CpG islands）的高甲基化是一类与癌症相关的常见表观遗传改变。高甲基化的全局模式具有肿瘤类型特异性且呈非随机分布。肿瘤特异性异常启动子甲基化的生物学意义与潜在机制仍未明确，但现有证据表明，该特异性可能涉及序列易感性差异、DNA甲基化活性靶向特定启动子序列，或是疾病进展过程中稀有DNA甲基化事件的筛选。我们通过对T细胞淋巴瘤组织培养样本及体内模型样本开展限制性地标基因组扫描（restriction landmark genomic scanning），发现MYC过表达会诱导产生一类特异性的CpG岛高甲基化特征。该特征可反映基因转录谱，且仅在疾病晚期被检测到。在MYC诱导的淋巴瘤中进一步失活Pten、p53与E2f2肿瘤抑制因子，可产生独特且具备诊断价值的CpG岛甲基化特征。我们的数据表明，淋巴瘤中的肿瘤特异性DNA甲基化，源于肿瘤发生过程中稀有DNA甲基化事件的筛选。该筛选过程似乎由肿瘤细胞的遗传构型所驱动，不仅为DNA高甲基化在肿瘤进展中的因果作用提供了实验证据，也解释了人类癌症演化过程中观测到的显著表观遗传异质性。基于少量遗传改变即可预测全基因组表观遗传沉默的能力，将助力更全面的肿瘤分类与肿瘤细胞生物学研究。