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Aberrant Promoter Methylation (aberrant + promoter_methylation)
Selected AbstractsAberrant promoter methylation of the TPEF gene in esophageal squamous cell carcinomaDISEASES OF THE ESOPHAGUS, Issue 7 2008B.-J. Zhao SUMMARY., Aberrant methylation of tumor suppressor genes plays an important role in the development of esophageal squamous cell carcinoma (ESCC). The purpose of the present study was to identify the epigenetic changes in ESCC. Methylation-sensitive arbitrarily primed polymerase chain reaction (MS AP-PCR) analysis was used on 22 matched ESCC tumors and adjacent normal tissues. Through this screen we identified a frequently methylated fragment that showed a high homology to the 5,-CpG island of the gene encoding a transmembrane protein containing epidermal growth factor and follistatin domains (TPEF). The methylation status of the TPEF gene was then detected by bisulfite sequencing and the levels of TPEF mRNA were detected by RT-PCR. In addition, the effects of a methylation inhibitor 5-aza-2,-deoxycytidine on TPEF mRNA expression was determined in cells of ESCC cell lines. Hypermethylation of the 5,-CpG island of TPEF was found in 12 of 22 (54.5%) primary tumors. Reverse transcription PCR analysis demonstrated that TPEF mRNA expression was significantly lower in tumors than in adjacent normal tissues, which is associated with promoter hypermethylation. In addition, treatment of ESCC cell lines with 5-aza-2,-deoxycytidine led to re-expression of the TPEF transcript. In conclusion, we observed promoter of TPEF gene is frequently hpermethylated, and is associated with the loss of TPEF mRNA expression in ESCC samples. Promoter hypermethylation of TPEF gene may play a role in the development of ESCC. [source] Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancersINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Kunitoshi Tomii Abstract Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. © 2006 Wiley-Liss, Inc. [source] Microsatellite instability of papillary subtype of human gastric adenocarcinoma and hMLH1 promoter hypermethylation in the surrounding mucosaPATHOLOGY INTERNATIONAL, Issue 4 2001Rong-Jun Guo Gastric cancer has striking heterogeneity in histological pattern, cellular phenotype, genotype, biomarkers, and biological behavior. We focused on the specific morphological papillary phenotype of gastric adenocarcinoma and attempted to identify its distinct molecular characteristics. In our comparative study, early stage papillary (papillary-dominant) gastric cancer showed a significantly higher and more widespread high-frequency microsatellite instability (MSI-H) than other morphological types. Analysis of mutations in a panel of five putative microsatellite instability (MSI)-associated genes in the MSI-H cases revealed that papillary or papillary-dominant cancer displays a unique profile of mutations compared to profiles previously reported in gastric cancer. Immunohistochemical staining and methylation analysis revealed that silencing of hMLH1 by methylation in its promoter region was responsible for the failure of mismatch repair in papillary-type gastric cancer, whereas aberrant promoter methylation of hMLH1 was not found in any cases without the unique mutator phenotype. Promoter hypermethylation of the hMLH1 genes was found to a lesser degree in the adjacent non-tumor mucosa in four of the 10 cases with tumor having the mutator phenotype. Microsatellite instability itself could not be detected in the adjacent non-tumor mucosa. Inactivation of hMLH1 expression by promoter hypermethylation may be an early event in carcinogenesis of this type of gastric cancer, preceding the development of the clear MSI phenotype of papillary carcinoma. [source] Prognostic significance of O6 -methylguanine DNA methyltransferase and p57 methylation in patients with diffuse large B-cell lymphomasAPMIS, Issue 2 2009SUN MI LEE To evaluate whether promoter methylation is related to responsiveness for chemotherapy or clinical outcome, we performed an association analysis between methylation and clinical outcomes. Patients with nodal diffuse large B-cell lymphomas (DLBCL) at a single institute (n=44) were studied for methylation of tumor-related genes, MGMT, p15INK4B, p16INK4A, p16INK4A, Mad2, TMS1/ASC, CASP8, and GSTP1. The clinical behavior of DLBCL after chemotherapy was followed up and analyzed. Hypermethylation of promoters of MGMT, p15INK4B, p16INK4A, p16INK4A, Mad2, and TMS1/ASC genes was observed in 52.3%, 31.8%, 54.5%, 47.7%, 50%, and 2.3% of the cases, respectively. Methylation of CASP8 and GSTP1 genes was not observed. Promoter methylation was not related to chemo-responsiveness, disease-free survival, and progress of disease after chemotherapy. However, in overall survival analyses, MGMT methylation (p<0.05) and responsiveness to chemotherapy (p<0.01) were significant prognostic factors in patients with DLBCL. In the low-risk group, patients with p57 methylation showed longer overall survival than patients without p57 methylation (p=0.02) and all patients with p57 methylation were alive during follow-up. Our results demonstrate that aberrant promoter methylation of MGMT and p57 is an additional biological marker for predicting increased overall survival in patients with DLBCL. [source] Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinomaCANCER, Issue 7 2004Riichiroh Maruyama M.D. Abstract BACKGROUND Methylation of CpG islands in the promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC). METHODS The methylation status of nine genes was determined in 124 surgically resected NSCLC cases using methylation-specific polymerase chain reaction. RESULTS The methylation frequencies of the genes tested in NSCLC specimens were 52% for E-cadherin (CDH1), 41% for RAS association domain family protein (RASSF1A), 38% for fragile histidine triad (FHIT) and adenomatous polyposis coli (APC), 27% for retinoic acid receptor beta (RAR,) and H-cadherin (CDH13), 20% for p16INK4A, 0.8% for O6 -methylguanine-DNA-methyltransferase (MGMT), and 0% for glutathione S-transferase P1 (GSTP1). The survival of the patients with FHIT methylation-positive tumors was found to be significantly shorter than that for those patients with methylation-negative tumors (P = 0.03), even in those patients with International Union Against Cancer TNM Stage I or Stage II disease (P = 0.007). In contrast, there were no significant survival differences noted between the methylation-positive and methylation-negative tumors for the other genes tested. In addition, based on multivariate analyses, FHIT methylation-positive status was found to be independently associated with poor survival (P = 0.046) and disease stage (P < 0.0001). CONCLUSIONS The results of the current study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC. Cancer 2004;100:1472,7. © 2004 American Cancer Society. [source] | ||||||||||