Diagnostic and Prognostic Information in Prostate Cancer with the Help of a Small Set of Hypermethylated Gene Loci

Abstract

Purpose: Our study was designed to evaluate promoter CpG island hypermethylation in the diagnosis and prognosis of prostate cancer. Experimental Design: Primary prostate cancers from 53 patients, pelvic lymph nodes, noncancerous prostate tissues, and prostate cell lines were analyzed. Real-time methylation-specific PCR was used to identify CpG island hypermethylation at five promising gene loci (i.e., GSTP1, APC, PTGS2, MDR1, and RASSF1a). Results: At three gene loci (GSTP1, APC, and PTGS1) and CpG island, hypermethylation was highly prevalent in prostate cancers (71-91%), and analysis of receiver operator curves showed that hypermethylation at these three gene loci can distinguish between prostate cancer and noncancerous prostatic tissue (i.e., benign hyperplasia) with a sensitivity of 71.1% to 96.2% and a specificity of 92.9% to 100%. Using sensitive SYBR green methylation-specific PCR technology, we observed a respective 28% and 71% hypermethylation rate at the RASSF1a and MDR1 loci in benign prostate hyperplasia, which may represent early nonaggressive carcinogenesis. Methylation characteristics in prostate cancer metastases (i.e., pelvic lymph nodes) were comparable to the respective primary cancer. Statistical analysis showed no correlation between the methylation status of a single gene locus and clinicopathologic variables (e.g., preoperative prostate specific antigen levels, Gleason score, capsular penetration, involvement of seminal vesicle, and age). In contrast, the methylation of two (GSTP1/APC ; GSTP1/PTGS2) or three (GSTP1/APC/PTGS2) gene loci correlated with prognostic indicators (i.e., pathologic stage, extraprostatic extension, and Gleason score, but not with prostate specific antigen levels). Conclusions: Our data suggest that the evaluation of DNA hypermethylation at three gene loci (i.e., GSTP1, APC, and PTGS2) is of diagnostic and prognostic value in prostate cancer.

DNA Methylation Changes Correlate with Gleason Score and Tumor Stage in Prostate Cancer

“…In addition, we found that APC methylation level was significantly higher in tumor tissues of stage pT3 or above (24.0%), compared with those with tumor stage pT2 (12.3%). However, Bastian et al (2005) did not find a link between GSTP1 or APC methylation and tumor progressive markers using methylation-specific PCR to measure DNA methylation.…”

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.…”

“…[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. The aim of the present study was to assess the methylation of APC and GSTP1 using quantitative PSQ to determine whether APC and GSTP1 methylation may be associated with prostate clinicopathological parameters and to evaluate the relevance of APC and GSTP1 methylation in discriminating between benign prostate hyperplasia (BPH) and PCa.…”

CpG Island hypermethylation in cell‐free serum DNA identifies patients with localized prostate cancer

“…The use of two or more methylated genes even increased diagnostic accuracy (e.g. ''GSTP1 and PTGS2'': sensitivity and specificity to 96-100%) [8,9]. Moreover, CGI hypermethylation in PCA tissue has prognostic relevance and correlates with pathological stage [8][9][10], tumor grade [8][9][10][11] and disease progression [8].…”