Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients
Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients
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DOI：
10.1002/ijc.10971
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发表时间：
2003-05-01
影响因子：
6.4
通讯作者：
To, KF
中科院分区：
文献类型：
--
作者：
Chan, MWY;Chan, LW;To, KF
RASSF1A所在的3p21.3区域的高频丢失在几个肿瘤中被证实。我们的目的是研究膀胱癌中RASSF1A的甲基化状态和3p21.3区域LOH的频率。对3株膀胱癌细胞株、40例膀胱TCC和14例配对空尿样本进行甲基化分析。通过甲基化特异性PCR，在细胞系T24和UMUC3中检测到RASSF1A基因启动子区完全甲基化。去甲基化处理在这2个细胞系中重新表达RASSF1A。在47.5%（19/40）的TCC病例中也检测到RASSF1A甲基化，但在6例原位癌（CIS）和6例正常尿路上皮样本中未检测到RASSF1A甲基化。在LOH研究中，57.9%（11/19）的病例检测到3p21.3区域缺失。有趣的是，72.7%（8/11）的LOH患者发现RASSF1A甲基化，而非LOH患者仅发现12.5%（1/8）甲基化。在50%（7/14）的空尿样本中检测到RASSF1A甲基化，但在正常对照中未检测到。它在检测癌细胞方面显示出比常规尿液细胞学更高的灵敏度，特别是对低级别病例。总之，我们的研究结果表明，膀胱癌中RASSF1A甲基化频率高，3p21.3区LOH频率高。这表明它可能是该染色体区域潜在的肿瘤抑制基因，并且可以通过启动子超甲基化沉默。在常规空尿中检测异常基因甲基化是可行的，可能为癌症检测提供一种无创、灵敏的方法。(C) 2003 Wiley-Liss, Inc。
High frequency loss of 3p21.3 region where RASSF1A located was demonstrated in several tumors. We aimed to investigate the methylation status of RASSF1A and the frequency of LOH in 3p21.3 region in bladder cancer. Three bladder cancer cell lines, 40 cases of bladder TCC and 14 cases of paired voided urine samples were subjected to methylation analysis. By methylation specific PCR, complete methylation of promoter region of RASSF1A gene were detected in cell lines T24 and UMUC3. Demethylation treatment re-expressed RASSF1A in these 2 cell lines. Methylation of RASSF1A was also detected in 47.5% (19/40) of the TCC cases but not in 6 carcinoma in situ (CIS) or 6 normal urothelium samples. For LOH study, loss of 3p21.3 region was detected in 57.9% (11/19) of our cases. Interestingly, methylation of RASSF1A was found in 72.7% (8/11) of the cases with LOH but only in 12.5% (1/8) of the cases without LOH. Methylation of RASSF1A was detected in 50% (7/14) of voided urine samples, but not in normal control. It showed a higher sensitivity than conventional urine cytology in detecting cancer cells, especially for low grade cases. In conclusion, our results demonstrated a high frequency of RASSF1A methylation with frequent LOH in 3p21.3 region in bladder cancer. It suggested that it may be a potential tumor suppressor gene in this chromosomal region and can be silenced by promoter hypermethylation. Detection of aberrant gene methylation in routine voided urine was feasible and may provide a non-invasive and sensitive approach for cancer detection. (C) 2003 Wiley-Liss, Inc.