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

Abstract

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

Combined Hypermethylation of APC and GSTP1 as a Molecular Marker for Prostate Cancer: Quantitative Pyrosequencing Analysis

“…4,5 To date, aberrant hypermethylation of CpG island-containing promoters has been identified at numerous loci in PCa, including GSTP1 and APC. [7][8][9][10][11] However, relatively limited studies have used the quantitative PSQ method to explore DNA hypermethylation status of various genes in PCa. 5,6 In the earlier studies using multiple genes by the PSQ method, it was demonstrated that both APC and GSTP1 methylation levels were significantly higher in PCa samples than in control samples.…”

“…7,8,10,11 Although it is typically relatively high in PCa and low in BPH, the reported strength of the association varies widely between studies. 7,8,10,11 As previously mentioned, the inconsistency in methylation results for these genes may be due to differences in detection methods, regions of interest, and/or tissue types. In the present study, the combination of APC and GSTP1 methylation by a quantitative method yielded a sensitivity of 92.8% while maintaining a specificity of 100% for the discrimination of PCa samples from benign prostate samples.…”

“…Methylation of these genes is associated with PCa. [5][6][7][8][9][10][11][12] Although a single molecular marker may be promising, the reliance on a single gene for the screening and diagnosis of PCa presents some limitations. [10][11][12] These limitations could potentially be overcome by the simultaneous use of multiple sensitive and specific molecular markers.…”

APC gene hypermethylation and prostate cancer: a systematic review and meta-analysis

“…Six could not provide data on the methylation among fluid samples (urine and blood), and 33-38 15 of the 29 articles using tissues had no raw data (the specific numbers of cases and controls with methylation were unclear, which made it difficult to calculate the data required for sensibility and specificity) or studied other factors such as the TMPRSS2 gene and urothelial carcinomas. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] Finally, 19 studies met the inclusion criteria and were included. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Among these 19 studies, 5 involved body fluid (blood, urine and so on) [11][12][13][14][15] and the remaining 14 articles involved sample tissues.…”

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

“…[7][8][9] In prostate cancer, hypermethylation of several genes has been associated with tumor aggressiveness in terms of clinical-pathological characteristics, biochemical recurrence, and/or mortality from prostate cancer. [10][11][12][13][14][15][16] Global hypomethylation, which may cause reactivation of the transcription of oncogenes and transposable elements and increases chromosomal instability and loss of imprinting, 17,18 has been less extensively investigated. We have recently conducted a systematic review of studies on prostatic tumor global hypomethylation and prostate cancer progression: 19 although studies were heterogeneous and mostly based on a limited sample size, global hypomethylation was reported to be associated with high Gleason score, advanced tumor stage, high pre-operative PSA, and presence of metastasis.…”