Baylin S B, Herman J G, Graff J R, Vertino P M, Issa J P
Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland, USA.
Adv Cancer Res. 1998;72:141-96.
Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
肿瘤细胞同时存在广泛的基因组低甲基化、更多局部区域的高甲基化以及DNA甲基转移酶（DNA-MTase）活性增加。这种“甲基化失衡”的每个组成部分可能从根本上促进肿瘤进展。低甲基化的确切作用尚不清楚，但这种变化很可能与肿瘤细胞中广泛的染色体改变有关。局部高甲基化的一个主要靶点是位于基因启动子区域的通常未甲基化的CpG岛。这种高甲基化与转录抑制相关，转录抑制可作为一种替代编码区突变的方式，使包括p16、p15、VHL和E-钙黏蛋白在内的肿瘤抑制基因失活。每个基因都可以通过去甲基化部分重新激活，基因功能丧失的选择性优势与经典突变导致的丧失相同。一般来说，异常甲基化，尤其是高甲基化，在肿瘤发生过程中是如何演变的才刚刚开始被阐明。正常情况下，未甲基化的CpG岛似乎受到保护，免受影响紧邻侧翼区域的密集甲基化。在肿瘤细胞中，这种保护作用丧失，可能是由于长期暴露于增加的DNA-MTase活性和/或局部保护机制的破坏。一些基因的高甲基化似乎仅在肿瘤发生演变后才出现，而其他一些基因，包括雌激素受体，在衰老过程中在正常细胞中就会发生高甲基化。后一种变化可能易导致肿瘤形成，因为肿瘤通常也会对这些相同的基因发生高甲基化。本文提出了一个模型，其中肿瘤进展是由这些甲基化异常与经典遗传变化之间的持续相互作用驱动的异质细胞群体的间歇性克隆扩增所导致的。
