Heterogeneous gene methylation patterns among pre‐invasive and cancerous lesions of the prostate: A histopathologic study of whole mount prostate specimens

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Abstract
BACKGROUND Gene methylation may contribute to prostate carcinogenesis through the silencing of gene transcription. We report on the methylation status of several genes shown to be silenced at different stages of progression using whole mount prostate specimens and laser capture microdissection. This is the first study to evaluate gene methylation patterns across multiple pre-cancerous and invasive cancer foci from the same prostate gland. METHODS Real-time PCR was used to evaluate methylation of five genes (GSTP1, RASSF1A, RARβ2, CD44, and EDNRB) across normal epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and multiple tumor foci from each of 11 prostate cancer patients. RESULTS Gene methylation was not found in normal epithelium. To our knowledge, this is the first report of RASSF1A and RARβ2 methylation in HGPIN lesions (30% prevalence for each gene). In addition, RASSF1A, RARβ2, and GSTP1 methylation was highly prevalent in tumor foci (>75% for all three genes). Methylation of CD44 and EDNRB was observed in 41 and 38% of tumors but was not present in HGPIN. CONCLUSIONS These data suggest that genes may be methylated at different points in the histopathologic progression of prostate cancer and these differences can be found in various histologic foci from the same gland.