Hypermethylation of the Human Glutathione S-Transferase-π Gene (GSTP1) CpG Island Is Present in a Subset of Proliferative Inflammatory Atrophy Lesions but Not in Normal or Hyperplastic Epithelium of the Prostate

Abstract

Somatic inactivation of the glutathione S-transferase-pi gene (GSTP1) via CpG island hypermethylation occurs early during prostate carcinogenesis, present in approximately 70% of high-grade prostatic intraepithelial neoplasia (high-grade PIN) lesions and more than 90% of adenocarcinomas. Recently, there has been a resurgence of the concept that foci of prostatic atrophy (referred to as proliferative inflammatory atrophy or PIA) may be precursor lesions for the development of prostate cancer and/or high-grade PIN. Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response. Because not all PIA cells are positive for GSTP1 protein, we hypothesized that some of the cells within these regions acquire GSTP1 CpG island hypermethylation, increasing the chance of progression to high-grade PIN and/or adenocarcinoma. Separate regions (n =199) from 27 formalin-fixed paraffin-embedded prostates were microdissected by laser-capture microdissection (Arcturus PixCell II). These regions included normal epithelium (n = 48), hyperplasticepithelium from benign prostatic hyperplasia nodules (n = 22), PIA (n = 64), high-grade PIN (n = 32), and adenocarcinoma (n = 33). Genomic DNA was isolated and assessed for GSTP1 CpG island hypermethylation by methylation-specific polymerase chain reaction. GSTP1 CpG island hypermethylation was not detected in normal epithelium (0 of 48) or in hyperplastic epithelium (0 of 22), but was found in 4 of 64 (6.3%) PIA lesions. The difference in the frequency of GSTP1 CpG island hypermethylation between normal or hyperplastic epithelium and PIA was statistically significant (P = 0.049). Similar to studies using nonmicrodissected cases, hypermethylation was found in 22 of 32 (68.8%) high-grade PIN lesions and in 30 of 33 (90.9%) adenocarcinoma lesions. Unlike normal or hyperplastic epithelium, GSTP1 CpG island hypermethylation can be detected in some PIA lesions. These data support the hypothesis that atrophic epithelium in a subset of PIA lesions may lead to high-grade PIN and/or adenocarcinoma. Because these atrophic lesions are so prevalent and extensive, even though only a small subset contains this somatic DNA alteration, the clinical impact may be substantial.

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

“…This implies that hypermethylation of IGFBP3 occurs as an early event in prostate carcinogenesis and supports a clonal relation between the tumour and HGPIN lesion. We also found methylation of GSTP1 in a high frequency of HGPIN foci, consistent with previous reports (Nakayama et al, 2003;Kang et al, 2004).…”

“…The high prevalence of GSTP1 hypermethylation in prostate cancer, HGPIN and in some proliferative inflammatory atrophy lesions indicates that it most likely precedes many other molecular aberrations in prostate carcinogenesis (Nakayama et al, 2003). Associated loss of GSTP1 activity and its protection from electrophilic and oxidative DNA damage would render cells susceptible to further transformations.…”

“…The most promising methylation biomarker identified to date is glutathione-S-transferase pi (GSTP1), detected in 490% of prostate tumours, 470% of HGPIN and at significantly lower frequencies and quantitatively much lower levels in normal prostate and benign prostatic hyperplasia (BPH) (Nakayama et al, 2003;Jeronimo et al, 2004). In addition, methylation of GSTP1 is highly specific to prostate cancer, rarely detected in other tumours (Esteller et al, 2001).…”

Angiotensin II Induces Oxidative Stress in Prostate Cancer

“…Novel observations have been reported regarding the pathologic entity of focal prostatic epithelial atrophy (57), which is associated with chronic inflammation with proliferative change, designated ''proliferative inflammatory atrophy.'' More interestingly, these areas are commonly adjacent to high-grade PIN or local foci of cancer in the prostate of older men (58). Proliferative inflammatory atrophy lesions have been regarded as a precursor lesion of prostate cancer (59).…”

Decreased NKX3.1 Protein Expression in Focal Prostatic Atrophy, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: Association with Gleason Score and Chromosome 8p Deletion

“…Some of these lesions are proposed as potential precursors to prostate cancer based on their frequent occurrence in proximity to carcinoma (23)(24)(25)(26) and molecular alterations (see below). Focal prostate atrophy commonly merges directly with low-and high-grade PIN (24,25,27), suggesting that some PIN lesions arise directly from atrophy. More rarely, focal atrophy seems to merge directly with small carcinoma lesions (23,(27)(28)(29).…”