肿瘤相关基因过甲基化的研究进展

The Roles of DNA Methylation in Human Neoplasms

最近的研究资料提示DNA序列的改变和Epigenetics(表遗传学或拟遗传学)的机制都参与肿瘤的发生。表遗传学研究基因表达的变化,这种变化可通过减数分裂遗传,但不涉及有关基因DNA序列的改变。DNA甲基化是表遗传学上研究最深入的一种机制,是一种酶介导的化学修饰过程,在DNA的某些碱基上增加一个甲基。在人类和大多数哺乳动物,DNA甲基化仅影响DNA链上鸟嘌呤前的胞嘧啶(CpG)。在启动子区域的DNA甲基化是抑制基因活性的一种重要机制。既往认为抑癌基因失活有两条途径:基因内突变和染色体物质丢失(杂合性丢失LOH或等位基因丢失)。现已确切证明DNA甲基化是肿瘤抑制基因失活的第三种机制,而且在某些情况下是抑癌基因失活的唯一的机制。各种类型肿瘤具有特征性的DNA甲基化模式;同一肿瘤类型,不同病人的肿瘤其甲基化模式也可不一样;DNA甲基化可在细胞恶变之前;因此,检测基因启动子甲基化可用于鉴别肿瘤类型和亚型,有助于早期发现有癌变倾向的细胞;还可作为分子指标预测对化疗的反应和判断预后等。5-氮-2'-脱氧胞苷等去甲基化药物作为抗肿瘤药物的效应,归因于两种机制:细胞毒性和诱导低甲基化。一些临床试验用去甲基化药物治疗实体肿瘤和恶性血液疾病,总体来说有效率不高。许多实验可评估基因的甲基化状态。

Recent data suggested that cancer appears to be a process that is fuelled both by genetic alterations and by epigenetic mechanisms. Epigenetics refer to the study of changes in gene expression that can be mitotically inherited, but is not associated with the changes in the coding sequence of the affected genes. DNA methylation, the best understood mechanism in epigenetics, is an enzyme mediated chemical modification that adds methyl (CH3) groups at selected sites on DNA. In humans and most mammals, DNA methylation only affects the cytosine base (C),when it is followed by a guanosine (G). DNA methylation in the promoter regions is a powerful mechanism for the suppression of gene activity. It was thought formerly that two pathways by which tumor suppressor genes became disabled were intragenic mutations and loss of chromosomal material [(loss of heterozygosity (LOH) or homozygous deletion)]. More recent studies have firmly established methylation as one potential hit and represent a third mechanism by which tumor suppressor genes are inactivated, and that, in some cases, methylation is the sole mechanism responsible for the inactivation of a tumor suppressor gene. There is clearly a tumor specific methylation pattern in many types of tumor. An individual tumor within a single patient may have characteristic set of gene with an increased propensity to become methylated as compared with a tumor of the same type in a different patient. Methylation changes appear to precede apparent malignancy in many cases. Therefore,methylation can distinguish tumor types and subtypes,and should be useful in improving early detection of potentially cancerous cells. Methylation markers may also be used to predict response to chemotherapy or duration of patient survival. The efficacy of hypomethylating agents (e.g. 5 aza 2′ deoxycytidine) as antineoplastic agents has been attributed to two distinct mechanism: cytotoxicity and induction of hypomethylation. Some clinical trials with them have been performed in solid tumors and malignant hematologic disease. In general, the response rates were not satisfactory. A variety of methods are used to evaluate the methylation status of genes. MSP (methylation specific PCR) is very sensitive and has been widely used. It takes advantage of the DNA sequence difference existing between methylated and unmethylated DNA after bisulfite treatment.