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

R. Henrique, F. R. Ribeiro, D. Fonseca, M. O. Hoque, A. L. Carvalho, V. L. Costa, M. Pinto, J. Oliveira, M. R. Teixeira, D. Sidransky, C. Jeronimo
2007 Clinical Cancer Research  
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
more » ... SF1A 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
doi:10.1158/1078-0432.ccr-07-1042 pmid:17947477 fatcat:kckl25f4nzerhdlrtmkunciojq