Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

Abstract

To date, several reports have been published about CpG island methylation of various genes in prostate cancer. However, most of these studies have focused on cancer tissue only or a single gene and data about concurrent methylation of multiple genes in prostate cancer or prostatic intraepithelial neoplasia (PIN) are limited. The aim of the present study was to determine the methylation profile of 11 tumour-related genes in prostate cancer and PIN. Seventy-one samples, including 37 prostate cancers, 14 PINs, and 20 normal prostates, were examined for the methylation status of 11 tumour-related genes using methylation-specific PCR. The mean number of genes methylated was significantly higher in prostate cancer and PIN than in non-neoplastic prostate (4.4, 3, and 0.2, respectively; p < 0.001). In prostate cancer, APC, GSTP1, MGMT, and RASSF1A were frequently methylated at a frequency of 56.8%, 86.5%, 75.7%, and 83.8%, respectively. These genes were methylated in more than 30% of PINs. Prostate cancers with high serum prostate-specific antigen (PSA) (more than 8 ng/ml) or a high Gleason score (GS) (3 + 4 or more) showed higher numbers of methylated genes than those with low serum PSA (8 or less) or low GS (3 + 3 or less) (5.4 versus 2.5 and 5.4 versus 3.1, respectively; p < 0.05). The methylation frequency of APC, RASSF1A, and RUNX3 was higher in prostate cancers with high serum PSA or with high GS than in those with low PSA or with low GS, respectively, the differences reaching statistical significance (p < 0.05). A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry. CpG island methylation is a frequent event, occurs early, and accumulates during multi-step prostatic carcinogenesis. High levels of CpG island hypermethylation might serve as a potential biological marker for aggressive prostate cancer.

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

“…Our data included paired tumor, nontumor tissues, and plasma samples from cases, which allowed us to investigate not only tumor/nontumor differences, but also the tissue-plasma correlations. The frequency of hypermethylation in PCa tissues for GSTP1, p16 (CDKN4A), and APC ranged from 83.3% to 95.8%, similar to previous studies, although different approaches were used for methylation detection ( Jeronimo et al, 2004;Kang et al, 2004;Maruyama et al, 2002). Consistent with previous research ( Jarrard et al, 1997;Chu et al, 2002;Kang et al, 2004;Chuang et al, 2007;Phe et al, 2010), we also found significant tumor/nontumor differences in gene-specific methylation levels (Fig.…”

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).…”

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

“…RUNX3 was also identified as one of the five most informative genes of the CpG island methylator phenotype of colorectal cancer (Weisenberger et al, 2006). In addition to gastric and colon cancer, RUNX3 is frequently inactivated in cancers of the lung, bladder, pancreas, liver, prostate, bile duct, breast, larynx, esophagus, and testicular yolk sac by either DNA hypermethylation or mislocalization of the protein in the cytoplasm (Kato et al, 2003;Goel et al, 2004;Kang et al, 2004;Li et al, 2004;Tozawa et al, 2004;Xiao and Liu, 2004;Ito et al, 2005;Kim et al, 2005b;Lau et al, 2006). Among the lung cancers, RUNX3 promoter hypermethylation is preferentially found in lung adenocarcinomas (Sato et al, 2006).…”