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Quantitative Methylation-Specific Polymerase Chain Reaction Gene Patterns in Urine Sediment Distinguish Prostate Cancer Patients From Control Subjects

From the Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD; and Bioinformatics and Computational Genomics, Department of Molecular Biotechnology, Faculty of Agricultural and Applied Biological Sciences, Gent University, Gent, Belgium

Address reprint requests to David Sidransky, MD, Director, Division of Head and Neck Cancer Research, The Johns Hopkins School of Medicine, 818 Ross Research Bldg, 720 Rutland Ave, Baltimore, MD 21205-2196; e-mail: dsidrans{at}jhmi.edu

PURPOSE: 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.

PATIENTS AND METHODS: We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14^ARF, MGMT, GSTP1, RARß2, 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.

RESULTS: 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 RARß2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels.

CONCLUSION: 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.

Supported by National Cancer Institute grant No. U01-CA84986 and Oncomethylome Sciences, SA.

M.O.H. and O.T. contributed equally to this study.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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