Hoque Mohammad Obaidul, Topaloglu Ozlem, Begum Shahnaz, Henrique Rui, Rosenbaum Eli, Van Criekinge Wim, Westra William H, Sidransky David
Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
J Clin Oncol. 2005 Sep 20;23(27):6569-75. doi: 10.1200/JCO.2005.07.009.
Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA.
We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls.
Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARbeta2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels.
Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.
在前列腺癌发病过程中，几种已知或推定的肿瘤抑制基因的启动子异常高甲基化频繁发生，是一种很有前景的癌症检测标志物。我们试图基于尿沉渣DNA中多个基因的定量甲基化特异性聚合酶链反应（QMSP）开发一种前列腺癌检测方法。
我们通过定量荧光实时聚合酶链反应检测了52例前列腺癌患者及21例配对原发性肿瘤的尿沉渣DNA中9个基因启动子（p16INK4a、p14(ARF)、MGMT、GSTP1、RARbeta2、CDH1 [E-钙黏蛋白]、TIMP3、Rassf1A和APC）的异常甲基化。我们还分析了91例年龄匹配且无泌尿生殖系统恶性肿瘤病史的个体的尿沉渣作为对照。
在所有52例前列腺癌患者的尿样中均检测到至少一种研究基因的启动子高甲基化。91例无泌尿生殖系统癌症证据的对照者的尿样中，未检测到p16、ARF、MGMT和GSTP1基因启动子的甲基化，而RARbeta2、TIMP3、CDH1、Rassf1A和APC的甲基化水平较低。
总体而言，尿样中发现的甲基化与原发性肿瘤中的甲基化状态相符。理论上，仅四个基因（p16、ARF、MGMT和GSTP1）的组合就能让我们以100%的特异性检测出87%的前列腺癌。我们的数据支持进一步开发用于尿液DNA中前列腺癌早期检测和监测的非侵入性QMSP检测方法。
