Payne Shannon R, Serth Jurgen, Schostak Martin, Kamradt Jorn, Strauss Arne, Thelen Paul, Model Fabian, Day J Kevin, Liebenberg Volker, Morotti Andrew, Yamamura Su, Lograsso Joe, Sledziewski Andrew, Semjonow Axel
Epigenomics, Inc., Seattle, Washington 98101, USA.
Prostate. 2009 Sep 1;69(12):1257-69. doi: 10.1002/pros.20967.
A prostate cancer (PCa) biomarker with improved specificity relative to PSA is a public health priority. Hypermethylated DNA can be detected in body fluids from PCa patients and may be a useful biomarker, although clinical performance varies between studies. We investigated the performance of candidate PCa DNA methylation biomarkers identified through a genome-wide search.
Real-time PCR was used to measure four DNA methylation biomarkers: GSTP1 and three previously unreported candidates associated with the genes RASSF2, HIST1H4K, and TFAP2E in sodium bisulfite-modified DNA. Matched plasma and urine collected prospectively from 142 patients referred for prostate biopsy and 50 young asymptomatic males were analyzed.
Analysis of all biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers discriminated PCa from biopsy negative patients with AUCs ranging from 0.64 for HIST1H4K (95% CI 0.55-0.72, P < 0.00001) to 0.69 for GSTP1 (95% CI 0.60-0.77, P < 0.00001). All biomarkers showed minimal correlation with PSA. Multivariate analysis did not yield a panel that significantly improved performance over that of single biomarkers. All biomarkers showed greater sensitivity for PCa in urine than in plasma DNA.
Analysis of the biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers provided information independent of PSA and may warrant inclusion in nomograms for predicting prostate biopsy outcome. The biomarkers' PCa sensitivity was greater for urine than plasma DNA. The biomarker performances in urine DNA should next be validated in formal training and test studies.
相对于前列腺特异性抗原（PSA）而言，具有更高特异性的前列腺癌（PCa）生物标志物是一项公共卫生优先事项。尽管不同研究之间的临床表现有所差异，但在PCa患者的体液中可以检测到DNA高甲基化，其可能是一种有用的生物标志物。我们研究了通过全基因组搜索鉴定出的候选PCa DNA甲基化生物标志物的性能。
采用实时聚合酶链反应（PCR）检测四种DNA甲基化生物标志物：谷胱甘肽S-转移酶P1（GSTP1）以及与RASSF2、HIST1H4K和TFAP2E基因相关的三个先前未报道的候选标志物，检测对象为亚硫酸氢盐修饰的DNA。对前瞻性收集的142例接受前列腺活检患者和50例年轻无症状男性的配对血浆和尿液进行分析。
对尿液DNA中的所有生物标志物进行分析，可显著区分PCa患者和活检阴性患者。这些生物标志物区分PCa患者和活检阴性患者的曲线下面积（AUC）范围为：HIST1H4K的AUC为0.64（95%置信区间0.55 - 0.72，P < 0.00001），GSTP1的AUC为0.69（95%置信区间0.60 - 0.77，P < 0.00001）。所有生物标志物与PSA的相关性均极小。多变量分析未得出一个比单一生物标志物性能有显著改善的组合。所有生物标志物在尿液中对PCa的敏感性均高于血浆DNA。
对尿液DNA中的生物标志物进行分析可显著区分PCa患者和活检阴性患者。这些生物标志物提供了独立于PSA的信息，可能有必要纳入预测前列腺活检结果的列线图中。这些生物标志物对尿液中PCa的敏感性高于血浆DNA。接下来应在正式的培训和测试研究中验证尿液DNA中生物标志物的性能。
