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Molecular Detection of Localized Prostate Cancer Using Quantitative Methylation-Specific PCR on Urinary Cells Obtained Following Prostate Massage

Authors' Affiliations: ¹ Institute for Cancer Studies and Academic Urology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, United Kingdom and ² CeRePP group, EA3104, University Paris VII; ³ Departments of Tumor Biology and ⁴ Urology, Groupement Hospitalier et Universitaire-Est Assistance Publique-Hôpitaux de Paris, University Paris VI; ⁵ Department of Urology, Hospital Henri Mondor, University Paris XII; and ⁶ Department of Urology, Institut Mutualiste Montsouris, University Paris V, Paris, France

Requests for reprints: Morgan Rouprêt, Institute for Cancer Studies, Royal Hallamshire Hospital, G Floor, Glossop Road, S10 2JF Sheffield, United Kingdom. Phone: 44-114-271-1648; Fax: 44-114-271-2268; E-mail: mroupret{at}club-internet.fr.

Purpose: The diagnosis of localized prostate cancer is difficult due to a lack of cancer-specific biomarkers. Many patients require repeat prostate biopsies to diagnose the disease. We investigated whether aberrant promoter hypermethylation in prostatic fluid could reliably detect prostate cancer.

Experimental Design: Urine samples were collected after prostate massage from 95 patients with localized prostate cancer undergoing radical prostatectomy (63 pT₁, 31 pT₂, and 1 pT₃) and from 38 control patients. Ten genes (GSTP1, RASSF1a, ECDH1, APC, DAPK, MGMT, p14, p16, RARß2, and TIMP3) were investigated using quantitative real-time methylation-specific PCR. Receiver operator curves were generated.

Results: The frequency of gene methylation ranged from 6.3% (p14) to 83.2% (GSTP1) in prostate cancer patients. At least one gene was hypermethylated in 93% of cancer patients. The specificity of methylation was 0.74. Methylation was significantly more frequent (P < 0.05) in cancer than control patients for all genes except p14 and p16. According to receiver operator curve analysis, the four-gene combination of GSTP1 (0.86), RASSF1a (0.85), RARß2 (0.80), and APC (0.74) best discriminated malignant from nonmalignant cases. The sensitivity and accuracy of this four-gene set were 86% and 89%, respectively.

Conclusions: The presence of aberrant methylation in urinary cells obtained after prostate massage is significantly associated with prostate cancer. A panel of four genes could stratify patients into low and high risk of having prostate cancer and optimize the need for repeat prostatic biopsies.

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