抑癌基因甲基化在肾细胞癌研究中的新进展

Aberrant Methylation of Tumor Suppressor Genes in Renal Cell Carcinoma

抑癌基因启动子高度甲基化被认为是除突变和缺失以外的抑癌基因功能失活的关键机制,在肿瘤的发生和发展中起重要作用,已成为目前肿瘤病因学基础研究的热点。肾细胞癌是泌尿系统最常见的恶性肿瘤之一,近年来也有许多文献报道了肾细胞癌中抑癌基因的异常甲基化情况。肾细胞癌临床发病隐匿,出现症状时多为晚期,肾细胞癌相关基因异常甲基化检测有望为肾癌的早期无创诊断提供新的途径。针对肾癌对放、化疗效果均不敏感的特点,改变DNA甲基转移酶活性和抑癌基因甲基化状况可作为肾细胞癌辅助治疗的一种新思路。本文对抑癌基因甲基化与肾细胞癌关系的研究进展作一综述,介绍DNA甲基化在肿瘤发生过程中的作用及机理;总结近7年来肾细胞癌中抑癌基因甲基化的研究情况和肾细胞癌独特的甲基化谱,并着重介绍了新近报道的HOXB13,HAI2/SPINT2,CDH1,CTNNG/JUP四个基因启动子异常甲基化与肾细胞癌的关系;阐述DNA甲基化研究对肾细胞癌的临床意义。

Promoter CpG methylation is a major epigenetic mechanism to inactivate the functions of tumor suppressor genes （TSG）, in addition to genetic mechanism （point mutation and deletion）, plays important roles in the pathogenesis of various tumors. Renal cell carcinoma （RCC） is a malignant tumor with poor prognosis, in which aberrant methylation of TSGs has also been widely reported. Most RCC patients are presented with advanced disease because early stage RCC does not have apparent symptoms, The detection of TSG methylation might provide new specific biomarkers for early non-invasive diagnosis of this disease. Because RCC is generally insensitive to conventional chemotherapy and radiotherapy, using epigenetic agents, such as azacytidine, to modulate the activities of DNA methyltransferases and reverse the methylation status of TSGs might be an attractive strategy for future treatment of RCC, which could be combined with conventional therapies. We reviewed recent advances in the research on TSG methylation in RCC, summarized the methylation profile of RCC-related genes, including HOXB13, HAI2/SPINT2, CDH1 and CTNNG/JUP, and discussed the clinical significance of aberrant CpG methylation for the diagnosis and treatment of RCC.