Epigenetic Heterogeneity of High-Grade Prostatic Intraepithelial Neoplasia: Clues for Clonal Progression in Prostate Carcinogenesis

Abstract

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma, but the frequency and timing of epigenetic changes found in prostate carcinogenesis has not been extensively documented. Thus, the promoters of three genes (APC, GSTP1, and RARb2) involved in prostate carcinogenesis were tested by quantitative methylation-specific PCR in tissue DNA from 30 prostate carcinomas, 128 high-grade PIN lesions, and 30 normal prostate tissue samples dissected from 30 radical prostatectomy specimens using laser capture microdissection. The percentage of methylated alleles (PMA) was calculated for each gene, and hierarchical cluster analysis was used to define the degree of similarity of epigenetic alterations among the various samples. We found that PMA values of APC and RARb2 were higher than those of GSTP1 in all three types of tissue samples and median PMA values for all three genes were higher in prostate cancer. By cluster analysis, 26 of 30 prostate carcinomas and 82 of 128 high-grade PIN lesions were grouped in the ''high methylation'' branch, whereas 24 of 30 normal prostate tissue samples were allocated in the ''low methylation'' branch. Although high-grade PIN lesions are epigenetically more similar to prostate carcinoma than to normal prostate tissue, paired prostate carcinoma and high-grade PIN lesions did not always segregate together. We concluded that APC and RARb2 hypermethylation is frequent in normal prostate tissue and the progressive enrichment in cells carrying methylated alleles observed in high-grade PIN and prostate carcinoma is consistent with clonal progression. Because GSTP1 promoter methylation is mainly observed in prostate carcinoma and some high-grade PIN lesions, it represents an important marker for the transition of in situ to invasive neoplasia.

DNA Methylation Markers for Prostate Cancer with a Stem Cell Twist

“…Indeed, most of the genes previously known to be methylated in PCa were also methylated in PIN, although less frequently (11,12). If confirmed in a larger series, the differential TACSTD2 finding will be an important step toward discriminating cells originating in PCa from cells originating in PIN lesions (e.g., in urine), thus increasing the specificity of methylation-based assays for early detection of PCa.…”

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

“…Although every effort was taken to ensure that tissue was only procured from within pathologically identified areas, we cannot rule out the possibility that minute amounts of occult carcinoma or HGPIN may have been present in some of the benign specimens. However, even studies that employed laser capture microdissection to isolate pure populations of cells have reported low levels of hypermethylation in morphologically normal prostate samples (Henrique et al, 2006). An alternative explanation is that certain molecular aberrations such as promoter hypermethylation may precede morphological changes, initially affecting a small subset of benign epithelial cells.…”

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

“…Our search strategy and application of the inclusion/exclusion criteria resulted in a total of 19 articles that were included in the systematic review. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] A description of the included studies is given in Tables 1 and 2. The following data were recorded for each study: author's name, year of publication, sample forms, method, 5 0 -3 0 primers (forward and reverse, respectively), amplicon size (bp) and annealing temperature (1C), country, race, cancer clinical classification, PSA, Gleason score, type of cases and controls, type of PCR method and other relevant characteristics of the study population.…”

“…[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. [16][17][18][19][20][21][22][23][24][25][26][27]…”

“…[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. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] Ten studies used quantitative real-time methylation-specific PCR (QMSP) to detect APC methylation, 11,13,14,18,19,[21][22][23]25,26 seven were conducted using the method of methylation-specific PCR (MSP), 12,15,...…”