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MGMT Expression (mgmt + expression)
Selected AbstractsRASSF1A, BLU, NORE1A, PTEN and MGMT Expression and Promoter Methylation in Gliomas and Glioma Cell Lines and Evidence of Deregulated Expression of de novo DNMTsBRAIN PATHOLOGY, Issue 2 2009Aiala Lorente Abstract Methylation of CpG islands in gene promoters can lead to gene silencing. Together with deletion or mutation, it may cause a loss of function of tumor suppressor genes. RASSF1A (3p21.3), NORE1A (1q32.1) and BLU (3p21.3) have been shown to be downregulated by methylation in cancer, and PTEN (10q23.3) and MGMT (10q26.1) are located in areas commonly deleted in astrocytomas. MGMT methylation predicts a better response and a longer overall survival in patients with glioblastomas treated with temozolomide. We analyzed 53 astrocytoma samples and 10 high-grade glioma cell lines. Gene expression was assessed by RT-PCR. Bisulfite sequencing, MSP and a melting curve analysis-based real-time PCR were performed to detect promoter methylation. Treatments with 5,-aza-2,-deoxicitidine were applied to restore gene expression in cell lines. Ninety-two percent of tumor samples were methylated for RASSF1A, 30%,57% for BLU and 47% for MGMT, suggesting promoter methylation of these genes to be a common event in glioma tumorigenesis. Only 4% of the tumors revealed a methylated promoter for NORE1A. No association between methylation and loss of expression could be established for PTEN. We identified de novo DNMTs overexpression in a subset of tumors which may explain the methylation phenotype of individual gliomas. [source] Protection of hematopoietic cells from O6 -alkylation damage by O6 -methylguanine DNA methyltransferase gene transfer: studies with different O6 -alkylating agents and retroviral backbonesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2001Michael Jansen Abstract: Overexpression of O6 -methylguanine DNA methyltransferase (MGMT) can protect hematopoietic cells from O6 -alkylation damage. To identify possible clinical applications of this technology we compared the effect of MGMT gene transfer on the hematotoxicity induced by different O6 -alkylating agents in clinical use: the chloroethylnitrosoureas ACNU, BCNU, CCNU and the tetrazine derivative temozolomide. In addition, various retroviral vectors expressing the MGMT-cDNA were investigated to identify optimal viral backbones for hematoprotection by MGMT expression. Protection from ACNU, BCNU, CCNU or temozolomide toxicity was evaluated utilizing a Moloney murine leukemia virus-based retroviral vector (N2/Zip-PGK-MGMT) to transduce primary murine bone marrow cells. Increased resistance in murine colony-forming units (CFU) was demonstrated for all four drugs. In comparison to mock-transduced controls, after transduction with N2/Zip-PGK-MGMT the IC50 for CFU increased on average 4.7-fold for ACNU, 2.5-fold for BCNU, 6.3-fold for CCNU and 1.5-fold for temozolomide. To study the effect of the retroviral backbone on hematoprotection various vectors expressing the human MGMT-cDNA from a murine embryonic sarcoma virus LTR (MSCV-MGMT) or a hybrid spleen focus-forming/murine embryonic sarcoma virus LTR (SF1-MGMT) were compared with the N2/Zip-PGK-MGMT vector. While all vectors increased resistance of transduced human CFU to ACNU, the SF1-MGMT construct was most efficient especially at high ACNU concentrations (8,12 µg/ml). Similar results were obtained for protection of murine high-proliferative-potential colony-forming cells. These data may help to optimize treatment design and retroviral constructs in future clinical studies aiming at hematoprotection by MGMT gene transfer. [source] Aberrant methylation and loss of expression of O6 -methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinomaPATHOLOGY INTERNATIONAL, Issue 6 2005Osamu Furonaka O6 -Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The methylation status of the MGMT gene was investigated by methylation-specific polymerase chain reaction (PCR) and expression status was investigated by immunohistochemistry in 70 cases of pulmonary squamous cell carcinoma (pulmonary SqCC), including 23 cases of the central type and 47 cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary adenocarcinoma (AC). The frequency of MGMT methylation was 36% in SqCC and 42% in AC. Cases with MGMT methylation correlated significantly with T factor in SqCC (P = 0.047) and AC (P = 0.03). In SqCC, the frequency of MGMT methylation was 26% in the central type and 40% in the peripheral type; a significant correlation was not found (P = 0.29). In AC with mixed subtypes showing MGMT methylation, the level of MGMT expression in the bronchioloalveolar carcinoma (BAC) area (non-invasive status) was significantly higher than that in the papillary or acinar AC area (invasive status; P = 0.0002). This trend was not found in AC with mixed subtypes showing no MGMT methylation (P = 0.10). These findings suggest that MGMT inactivation is an event that occurs in the late carcinogenic process in SqCC and AC, and that AC progress from non-invasive status to invasive status with MGMT inactivation induced by the promoter DNA methylation. [source] Impact of Morphology, MIB-1, p53 and MGMT on Outcome in Pilocytic AstrocytomasBRAIN PATHOLOGY, Issue 3 2010Craig Horbinski MD Abstract Pilocytic astrocytoma (PA) is the most common glioma in the pediatric population. PAs can exhibit variable behavior that does not always correlate with location, yet at present there is no way to predict which tumors will be more aggressive. To address this problem, an institutional cohort of 147 PAs (118 with outcome data) from both cerebellar and noncerebellar locations (spine, diencephalon, midbrain, brainstem and cortex) was utilized. Parameters included quantification of characteristic morphologic variables as well as genes previously shown to be of relevance in high-grade gliomas, including MIB-1, p53 and MGMT. In this cohort, the classic biphasic appearance was most common in cerebellar tumors, whereas noncerebellar tumors were predominantly microcystic. Associations with outcome suggest that the presence of degenerative atypia may be a favorable factor in PAs. Oligodendroglial morphology and the absence of leptomeningeal invasion are adverse histologic factors, but only in cerebellar tumors. Conversely, MIB-1 proliferation index and p53 and MGMT expression do not correlate with outcome. Morphologic biomarkers thus do exist for PAs, but the utility of each biomarker varies according to location. These results suggest that PAs differ fundamentally according to location; therefore, biological behavior may not simply depend on extent of resection. [source] | ||||||||||