Hypermethylation of the RASSF1A tumor suppressor gene in Japanese clear cell renal cell carcinoma.
Hypermethylation of the RASSF1A tumor suppressor gene in Japanese clear cell renal cell carcinoma.
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DOI：
10.3892/or.12.4.805
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发表时间：
2004-10
期刊：
影响因子：
4.2
通讯作者：
K. Tokinaga;H. Okuda;Asuka Nomura;S. Ashida;M. Furihata;T. Shuin
中科院分区：
文献类型：
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作者：
K. Tokinaga;H. Okuda;Asuka Nomura;S. Ashida;M. Furihata;T. Shuin
在一些人类恶性肿瘤中已经观察到染色体3p21.3上RASSF1A肿瘤抑制基因的高甲基化相关失活。在透明细胞肾癌（RCC）中，RASSF1A基因启动子区甲基化状态的频率相对较高（91%）或较低（23%），这取决于报告的国家。为了明确RASSF1A基因高甲基化在日本RCC发展中的确切贡献，我们分析了50个日本透明细胞RCC和RCC细胞系中RASSF1A启动子区域的甲基化状态。虽然观察到RASSF1A启动子的高甲基化频率相对较高（50个肿瘤中有39个，78%），但大多数匹配的近端正常组织DNA也显示出弱甲基化。通过与适应正常肾组织DNA的甲基化水平比较，RASSF1A启动子的肿瘤优先超甲基化被认为是40%（20/50组匹配）的原代透明细胞rcc。在I-II期或III-IV期肿瘤中，分别有36%（15/42）和64%（5/8）观察到RASSF1A启动子的高甲基化，在病理分级为I级或II级的肿瘤样本中分别有42%（11/26）和38%（9/24）观察到RASSF1A启动子的高甲基化。此外，19个RCC细胞系中有16个（84%）显示RASSF1A启动子区域完全或部分甲基化。在原发性RCC或RCC细胞系中，RASSF1A甲基化频率与VHL肿瘤抑制基因失活之间没有关联。我们的研究结果显示，肿瘤特异性RASSF1A启动子在高达40%的低级别或低阶段透明细胞rcc中发生了高甲基化。比较肿瘤与正常组织中RASSF1A启动子的甲基化状态是了解肿瘤特异性高甲基化的必要条件。由于相当多的正常肾脏被高甲基化，RASSF1A对肾癌发生和进展的贡献可能比预期的要复杂。
Hypermethylation associated inactivation of RASSF1A tumor suppressor gene at chromosome 3p21.3 has been observed in several human malignancies. Relatively high (91%) or low (23%) frequencies were reported in the methylation status of promoter region of the RASSF1A gene in clear cell renal carcinoma (RCC) depending on the country the report was from. To clarify exact contribution of the hypermethylation of RASSF1A gene in the development of RCC in Japan, we analyzed the methylation status of the RASSF1A promoter region in 50 Japanese clear cell RCC and RCC cell lines. Although relatively high frequency of hypermethylation in RASSF1A promoter (39 of 50 tumors, 78%) was observed, most of matched proximal normal tissue DNA also showed weak methylation. By comparison with methylation level of adapted normal kidney tissue DNA, tumor preferential hypermethylation in RASSF1A promoter was recognized as 40% (20/50 matched sets) of primary clear cell RCCs. Hypermethylation in RASSF1A promoter was observed in 36% (15/42) and 64% (5/8) of stage I-II or III-IV tumors, and also observed in 42% (11/26) and 38% (9/24) of our tumor samples with pathological grade I or II, respectively. In addition, 16 of 19 RCC cell lines (84%) showed complete or partial methylation of RASSF1A promoter region. There was no association between the frequency of RASSF1A methylation and inactivation of VHL tumor suppressor gene in either primary RCCs or RCC cell lines. Our results showed tumor specific RASSF1A promoter hypermethylation in up to 40% of low grade or low stage clear cell RCCs. It is essential to compare the methylation status of RASSF1A promoter in tumor with normal tissue to understand tumor specific hypermethylation. Since considerable cases of normal kidney are hypermethylated, contribution of the RASSF1A for the development and progression of kidney cancer may be more complex than expected.