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High Promoter Methylation Levels of APC Predict Poor Prognosis in Sextant Biopsies from Prostate Cancer Patients

Authors' Affiliations: Departments of ¹ Pathology, ² Genetics, ³ Radiology, and ⁴ Urology, Portuguese Oncology Institute–Porto, ⁵ Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, and ⁶ School of Health Sciences, Fernando Pessoa University, Porto, Portugal; and ⁷ Division of Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Carmen Jerónimo, Department of Genetics, Portuguese Oncology Institute–Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. Phone: 351-225084000; Fax: 351-225084016; E-mail: cjeroni{at}ufp.pt.

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 disease-specific 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.