Schulz W A
Urologische Klinik, Heinrich-Heine-Universitat, D-40225 Dusseldorf, Germany.
Int J Oncol. 1998 Jul;13(1):151-67.
Three different kinds of alterations in DNA methylation have been observed in urological malignancies. DNA hypermethylation of CpG-rich promoter regions is an important mechanism involved in the inactivation of tumor suppressor and other genes in prostate, renal cell, and bladder carcinoma. Genome-wide hypomethylation is most pronounced in urothelial carcinoma, but also occurs in prostatic cancer. Loss of imprinting may be a primary event in the aetiogenesis of Wilms' tumor and probably contributes to testicular cancer. With respect to alterations in DNA methylation three tumor categories are distinguished: in the development of embryonic tumors, e.g. Wilms' tumor, loss of imprinting is important probably by upsetting the balance between genes promoting or inhibiting proliferation. In tumors with faulty DNA methylation, e.g. renal cell carcinoma, occasional errors in DNA methylation are selected for during tumor development. In tumors with deranged methylation, e. g. in most bladder and prostate carcinomas, the mechanisms establishing methylation patterns are fundamentally disturbed and multiple alterations in DNA methylation are observed. At least one of the enzymes establishing methylation patterns, viz. DNA methyltransferases and demethylases, may be deregulated. Moreover, changes in methyl group metabolism need to be considered. DNA hypermethylation and loss of imprinting act by altering the expression of selected genes, whereas hypomethylation may facilitate transcription and recombination throughout the genome by its effect on the chromatin structure. The combination of all three types of alterations may create genomic instability in tumors with deranged DNA methylation. Regarding a potential clinical use, detection of hypermethylation appears most promising in cancer diagnosis, while parameters reflecting genome-wide hypomethylation may prove useful in the prediction of prognosis. Inhibitors of DNA methylation are being improved and will presumably first be employed against tumors with hypermethylated key tumor suppressor genes.
在泌尿系统恶性肿瘤中已观察到三种不同类型的DNA甲基化改变。富含CpG的启动子区域的DNA高甲基化是前列腺癌、肾细胞癌和膀胱癌中肿瘤抑制基因及其他基因失活的重要机制。全基因组低甲基化在尿路上皮癌中最为明显，但也见于前列腺癌。印记缺失可能是肾母细胞瘤发病机制中的一个主要事件，可能也与睾丸癌的发生有关。关于DNA甲基化改变，可区分出三类肿瘤：在胚胎性肿瘤如肾母细胞瘤的发生过程中，印记缺失可能通过破坏促进或抑制增殖的基因之间的平衡而发挥重要作用。在DNA甲基化存在缺陷的肿瘤如肾细胞癌中，肿瘤发展过程中会选择DNA甲基化的偶尔错误。在甲基化紊乱的肿瘤如大多数膀胱癌和前列腺癌中，建立甲基化模式的机制从根本上受到干扰，可观察到DNA甲基化的多种改变。至少一种建立甲基化模式的酶，即DNA甲基转移酶和去甲基化酶，可能失调。此外，还需要考虑甲基代谢的变化。DNA高甲基化和印记缺失通过改变特定基因的表达发挥作用，而低甲基化可能通过对染色质结构的影响促进全基因组的转录和重组。这三种改变类型的组合可能会在DNA甲基化紊乱的肿瘤中产生基因组不稳定。关于潜在的临床应用，高甲基化检测在癌症诊断中似乎最具前景，而反映全基因组低甲基化的参数可能在预后预测中有用。DNA甲基化抑制剂正在不断改进，可能首先用于治疗关键肿瘤抑制基因高甲基化的肿瘤。
