High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients
High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients
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DOI：
10.1158/1078-0432.ccr-07-1042
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发表时间：
2007-10-15
影响因子：
11.5
通讯作者：
Jeronimo, Carmen
中科院分区：
文献类型：
--
作者：
Henrique, Rui;Ribeiro, Franclim R.;Jeronimo, Carmen
目的：前列腺癌是一种高度流行的恶性肿瘤，构成了癌症相关的发病率和死亡率的主要原因。由于目前临床、血清学和病理学参数在预测疾病进展方面的局限性，我们试图通过定量甲基化特异性PCR（QMSP）在前列腺活检中研究一小组基因的启动子甲基化的预后价值。在一个前瞻性系列的83例前列腺癌患者提交的六分活检中，通过QMSP测定APC、CCND 2、GSTP 1、RARB 2和RASSF 1A的启动子甲基化水平。临床病理学数据[年龄、血清前列腺特异性抗原（PSA）、分期和Gleason评分]和前列腺癌进展和/或死亡时间与甲基化结果相关。Log-rank检验和考克斯回归模型用于确定哪些表观遗传标记物是预后的独立预测因子。结果：在中位随访时间为45个月时，15例（18%）患者死于前列腺癌，37例（45%）患者复发。在单变量分析中，APC的分期和高甲基化与较差的疾病特异性生存率显著相关，而分期、Gleason评分、高诊断性血清PSA水平以及APC、GSTP 1和RASSF 1A的高甲基化与较差的无病生存率显著相关。然而，在最终的多变量分析中，只有临床分期和APC的高甲基化与不良预后显著独立相关，即，结论：高水平APC启动子甲基化是前列腺活检样本中预后不良的独立预测因子，并可能为患者管理提供相关的预后信息。
Purpose: Prostate cancer is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. Owing to the limitations of current clinical, serologic, and pathologic parameters in predicting disease progression, we sought to investigate the prognostic value of promoter methylation of a small panel of genes by quantitative methylation-specific PCR (QMSP) in prostate biopsies.Experimental Design: Promoter methylation levels of APC, CCND2, GSTP1, RARB2, and RASSF1A were determined by QMSP in a prospective series of 83 prostate cancer patients submitted to sextant biopsy. Clinicopathologic data [age, serum prostate-specific antigen (PSA), stage, and Gleason score] and time to progression and/or death from prostate cancer were correlated with methylation findings. Log-rank test and Cox regression model were used to identify which epigenetic markers were independent predictors of prognosis.Results: At a median follow-up time of 45 months, 15 (18%) patients died from prostate cancer, and 37 (45%) patients had recurrent disease. In univariate analysis, stage and hype rmethylation of APC were significantly associated with worse disease -specific survival, whereas stage, Gleason score, high diagnostic serum PSA levels, and hypermethylation of APC, GSTP1, and RASSF1A were significantly associated with poor disease-free survival. However, in the final multivariate analysis, only clinical stage and high methylation of APC were significantly and independently associated with unfavorable prognosis, i.e., decreased disease-free and disease-specific survival.Conclusions: High-level APC promoter methylation is an independent predictor of poor prognosis in prostate biopsy samples and might provide relevant prognostic information for patient management.