The role of RASSF1A methylation in cancer.
The role of RASSF1A methylation in cancer.
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DOI：
10.1155/2007/291538
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Latif F
中科院分区：
文献类型：
--
作者：
Hesson LB;Cooper WN;Latif F
肿瘤抑制基因失活对癌症的发病至关重要；这种功能丧失可能是由基因缺失或突变等不可逆过程介导的。另外，肿瘤抑制基因可能通过表观遗传过程失活，这是一种可逆机制，有望更容易接受治疗剂的治疗。CpG二核苷酸在基因组中的表达不足，但在一些基因的启动子内发现了CpG二核苷酸，这些CpG岛的甲基化在基因表达的控制中起着关键作用。DNA甲基转移酶DNMT1和DNMT3b的抑制剂已用于临床，这些核苷酸类似物缺乏特异性，但低剂量治疗的副作用很小，2004年，Vidaza（5-阿扎胞苷）获准用于骨髓增生异常综合征。甲基化抑制剂也与另一类表观遗传修饰剂组蛋白去乙酰化酶抑制剂一起进入试验，这种表观遗传双子弹为改善治疗方案提供了希望。最近有大量的报道表明，在癌症的发展中起重要作用的基因的表观遗传失活，包括ras相关结构域家族的基因。RASSF1A （Ras-association domain family 1, isoform A）的表观遗传失活是癌症中最常见的分子变化之一。RASSF1A启动子CpG岛的高甲基化沉默了该基因在许多癌症中的表达，包括肺癌、乳腺癌、前列腺癌、胶质瘤、神经母细胞瘤和肾癌。最近的几项研究已经阐明了RASSF1A甲基化的诊断和预后潜力。这表明RASSF1A甲基化是早期癌症检测的一个有吸引力的生物标志物，对大多数癌症来说，这可以改善临床结果。DNA甲基化分析适用于一系列体液，包括血清、尿液、细支气管肺泡灌洗液和痰。这些体液的容易获取否定了需要侵入性程序来获得活检材料。本文将讨论使用RASSF1A甲基化作为癌症诊断和预后标志物的可行性。
Tumour suppressor gene inactivation is critical to the pathogenesis of cancers; such loss of function may be mediated by irreversible processes such as gene deletion or mutation. Alternatively tumour suppressor genes may be inactivated via epigenetic processes a reversible mechanism that promises to be more amenable to treatment by therapeutic agents. The CpG dinucleotide is under-represented in the genome, but it is found in clusters within the promoters of some genes, and methylation of these CpG islands play a critical role in the control of gene expression. Inhibitors of the DNA methyltransferases DNMT1 and DNMT3b have been used in a clinical setting, these nucleotide analogues lack specificity but the side effects of low dose treatments were minimal and in 2004 Vidaza (5-azacitidine) was licensed for use in myelodysplastic syndrome. Methylation inhibitors are also entering trials in conjunction with another class of epigenetic modifiers, the histone deacetylase inhibitors and this epigenetic double bullet offers hope of improved treatment regimes. Recently there has been a plethora of reports demonstrating epigenetic inactivation of genes that play important roles in development of cancer, including Ras-association domain family of genes. Epigenetic inactivation of RASSF1A (Ras-association domain family 1, isoform A) is one of the most common molecular changes in cancer. Hypermethylation of the RASSF1A promoter CpG island silences expression of the gene in many cancers including lung, breast, prostate, glioma, neuroblastoma and kidney cancer. Several recent studies have illustrated the diagnostic and prognostic potential of RASSF1A methylation. This presents RASSF1A methylation as an attractive biomarker for early cancer detection which, for most cancers, results in improved clinical outcome. DNA methylation analysis is applicable to a range of body fluids including serum, urine, bronchioalveolar lavage and sputum. The ease with which these body fluids can be acquired negates the need for invasive procedures to obtain biopsy material. This review will discuss the feasibility of using RASSF1A methylation as a diagnostic and prognostic marker in cancer management.
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