术前血清DNA中GSTP1基因启动子区域CpG岛高甲基化与根治性前列腺切除术后早期前列腺特异性抗原复发风险

Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy.

作者信息

Bastian Patrick J, Palapattu Ganesh S, Lin Xiaohui, Yegnasubramanian Srinivasan, Mangold Leslie A, Trock Bruce, Eisenberger Mario A, Partin Alan W, Nelson William G

机构信息

The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, USA.

出版信息

Clin Cancer Res. 2005 Jun 1;11(11):4037-43. doi: 10.1158/1078-0432.CCR-04-2446.

DOI:10.1158/1078-0432.CCR-04-2446

PMID:15930338

Abstract

PURPOSE

Hypermethylation of the CpG island at the promoter region of the pi-class glutathione S-transferase gene (GSTP1) is the most common somatic genome abnormality in human prostate cancer. We evaluated circulating cell-free DNA GSTP1 CpG island hypermethylation as a prognostic biomarker in the serum of men with prostate cancer.

EXPERIMENTAL DESIGN

Prostate cancer DNA GSTP1 CpG island hypermethylation was detected using a restriction endonuclease quantitative PCR technique. We analyzed preoperative serum from 85 men with clinically localized prostate cancer treated with radical prostatectomy and from 35 men with a negative prostate biopsy. We then assayed preoperative serum from a data set of 55 pairs of men with clinically localized prostate cancer treated with radical prostatectomy, matched for Gleason score, comprising 55 men suffering prostate-specific antigen (PSA) recurrence (median, 2 years) and 55 men who were free of disease at last follow-up (median, 3 years). The association of serum GSTP1 CpG island hypermethylation and PSA recurrence was determined.

RESULTS

Circulating cell-free DNA with GSTP1 CpG island hypermethylation was not detected in the serum of men with a negative prostate biopsy but was detected in 12% of men with clinically localized disease and 28% of men with metastatic cancer (P = 0.003). In the matched data set, eight men (15%) who developed PSA recurrence were positive for DNA with GSTP1 CpG hypermethylation, whereas no patient who was free of disease was positive for GSTP1 CpG island hypermethylation (McNemar test, chi(2) = 6.1, P = 0.01). In a multivariable analysis that accounted for recognized prognostic factors, the presence of serum DNA with GTSP1 CpG island hypermethylation was the most significant predictor of PSA recurrence (hazard ratio, 4.4; 95% confidence interval, 2.2, 8.8; P < 0.001).

CONCLUSION

Our study suggests that GSTP1 CpG island hypermethylation may be an important DNA-based prognostic serum biomarker for prostate cancer.

摘要

目的

π类谷胱甘肽S-转移酶基因（GSTP1）启动子区域CpG岛的高甲基化是人类前列腺癌中最常见的体细胞基因组异常。我们评估了循环游离DNA GSTP1 CpG岛高甲基化作为前列腺癌男性血清中的一种预后生物标志物。

实验设计

采用限制性内切酶定量PCR技术检测前列腺癌DNA GSTP1 CpG岛高甲基化。我们分析了85例接受根治性前列腺切除术治疗的临床局限性前列腺癌男性和35例前列腺活检阴性男性的术前血清。然后，我们对55对接受根治性前列腺切除术治疗的临床局限性前列腺癌男性数据集的术前血清进行了检测，这些男性根据Gleason评分进行匹配，包括55例发生前列腺特异性抗原（PSA）复发的男性（中位数为2年）和55例在最后一次随访时无疾病的男性（中位数为3年）。确定了血清GSTP1 CpG岛高甲基化与PSA复发之间的关联。

结果

前列腺活检阴性男性的血清中未检测到具有GSTP1 CpG岛高甲基化的循环游离DNA，但在12%的临床局限性疾病男性和28%的转移性癌症男性中检测到（P = 0.003）。在匹配的数据集中，8例发生PSA复发的男性（15%）的DNA GSTP1 CpG高甲基化呈阳性，而无疾病的患者中没有一例GSTP1 CpG岛高甲基化呈阳性（McNemar检验，χ² = 6.1，P = 0.01）。在一项考虑了公认预后因素的多变量分析中，存在具有GTSP1 CpG岛高甲基化的血清DNA是PSA复发的最显著预测因子（风险比，4.4；95%置信区间，2.2，8.8；P < 0.001）。