Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer
Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer
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DOI：
10.1016/j.juro.2007.08.091
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发表时间：
2008-01-01
影响因子：
6.6
通讯作者：
Bastian, Patrick J.
中科院分区：
文献类型：
--
作者：
Ellinger, Joerg;El Kassem, Nadja;Bastian, Patrick J.
目的：CpG岛甲基化是膀胱癌发生发展过程中的常见事件。我们探讨了膀胱癌患者的血清游离DNA超甲基化的诊断和预后价值。材料和方法：研究队列包括45例膀胱癌患者进行cytomerase和45例组织学证实的良性前列腺增生作为对照。结果：APC和GSTP 1基因启动子区甲基化率为59%，而TIG 1（32%）、PTGS 2（24%）和DAPK（2%）基因启动子区甲基化率较低。在良性前列腺增生组中，有3例患者还存在甲基化的GST P1 DNA，而其他基因位点均未甲基化。APC、GSTP 1或TIG 1的高甲基化最准确地区分膀胱癌患者和对照组，灵敏度为80%，特异性为93%。高甲基化与预后不良的临床病理参数显著相关，包括A-PC与pT分期，GST 1，或GST 1或TIG 1与多灶性膀胱癌和A-PC，或A-PC或TIG 1与手术切缘阳性。APC基因高甲基化患者的膀胱癌特异性死亡率显著增加。结论：检测血清游离DNA的高甲基化可提供有价值的诊断和预后信息，结合3个基因位点（APC、GSTP 1和TIG 1）的结果仍能提高诊断和预后。膀胱癌患者血清中存在高甲基化DNA与更差的结果相关。我们的研究结果表明，测量膀胱癌患者血清中的超甲基化是一种有用的生物标志物。
Purpose: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer.Materials and Methods: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment.Results: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%, PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including A-PC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and A-PC, or A-PC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation.Conclusions: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker.