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 hypermethylation 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 diseasespecific 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.Prostate cancer (PCa) is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality, accounting for 33% of all cancers diagnosed and for nearly 10% of all cancer deaths in U.S. males (1). Although serum prostate-specific antigen (PSA) is generally recommended for PCa screening, confirmation of diagnosis requires a prostate biopsy (2). The relevance of this biopsy exceeds its diagnostic purposes because the assessment of tumor grade and extent has a substantial impact on therapeutic decision making. However, the information provided by prostate biopsy meets with important limitations owing to intra-and interobserver variability in Gleason grading and sampling error (3, 4). Moreover, other accepted prognostic factors (e.g., clinical stage and pretherapeutic serum PSA levels) that influence treatment decisions are rather imperfect in predicting disease progression. The ability to predict disease-specific and disease-free survival at diagnosis is Imaging, Diagnosis, Prognosis

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Retinoic acid receptor ␤2 (RAR␤2) is a tumor suppressor gene frequently hypermethylated in several human neoplasms. To further characterize this epigenetic alteration in prostate cancer progression, we examined tumor tissue from 118 patients with prostate carcinoma (PCa), 38 paired highgrade prostatic intraepithelial neoplasias (HGPIN), and nonneoplastic prostate tissue from 30 patients with benign prostate hyperplasia (BPH), using quantitative methylation-specific PCR. We found RAR␤2 hypermethylation in 97.5% of PCa, 94.7% of HGPIN, and 23.3% of BPH. Methylation levels were significantly higher in PCa compared with HGPIN and BPH (P < 0.00001). By establishing an empiric cutoff value, we were able to discriminate between neoplastic and non-neoplastic tissue, with 94.9% sensitivity and 100% specificity. Moreover, RAR␤2 methylation levels correlated with higher pathological stage (r ‫؍‬ 0.30, P ‫؍‬ 0.0009). This quantitative assay represents a novel and promising molecular marker that may augment current approaches for prostate cancer detection.

Purpose: The main procedure to confirm a suspected diagnosis of prostate cancer is histologic analysis of ultrasound-guided sextant prostate biopsies. As it is difficult to reliably assess tumor stage and grade in such minute samples, the clinical significance of some tumor foci remains unclear. Genetic markers that could augment pretreatment prognostic information would improve the clinical management of the disease. Experimental Design: We have analyzed by comparative genomic hybridization a consecutive series of prostate needle biopsies obtained prospectively from 100 prostate cancer suspects. For 25 of these patients, a second independent biopsy core was analyzed to assess possible tumor heterogeneity. Additionally, a three-color fluorescent in situ hybridization assay was done in paraffin-embedded biopsy cores to validate the comparative genomic hybridization findings and to confirm their prognostic value. Results: Sixty-one of 100 biopsy samples had morphologic evidence of prostate cancer and 41 (67%) of these displayed genomic copy number changes as opposed to none of the morphologically normal biopsies. The presence of losses, amplifications, and the total number of genomic imbalances were significantly associated with poorly differentiated tumors. Kaplan-Meier curves with log-rank test showed that patients whose tumors displayed 8q gains had a significantly worse survival even when tumor grade was taken into account (P = 0.008). Restricting the analysis to cases with Gleason score 7, the most troublesome category in terms of prognostic information, gains at 8q were still significantly associated with poor survival (P = 0.011), something that was confirmed by fluorescent in situ hybridization in an independent series of biopsies with much longer follow-up time (P = 0.023). Conclusions: We show that whole genomic information can be obtained from minute needle biopsies of prostate cancer suspects and that genetic data can provide additional prognostic information before a therapeutic decision is taken.