MGMT gene silencing and benefit from temozolomide in glioblastoma
ABSTRACT Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.
We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis.
The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.
Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
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ABSTRACT: This analysis evaluated the efficacy and safety of bevacizumab as monotherapy and with irinotecan for recurrent glioblastoma in community-based practices. Adult patients with bevacizumab-naive, recurrent glioblastoma initiating second-line treatment (July 2006-June 2010) were identified using McKesson Specialty Health/US Oncology Network health records. Overall (OS) and progression-free survival (PFS) estimates were analyzed through July 2011 and compared for bevacizumab and non-bevacizumab regimens using the log-rank test. An adjusted Cox proportional hazards model assessed the effects of patient and treatment characteristics on outcomes. The analysis identified 159 patients initiating second-line treatment with a bevacizumab-monotherapy (n = 57), bevacizumab-combination (n = 79), or non-bevacizumab (n = 23) regimen. Patient characteristics were generally similar across groups. In the Cox analyses, OS (hazard ratio [HR] 0.51 [95 % confidence interval (CI) 0.31-0.82]; univariate medians: 8.86 vs. 5.19 months) was significantly longer with bevacizumab-containing regimens. Median PFS was longer with bevacizumab-containing regimens, but did not reach statistical significance (HR 0.64 [95 % CI 0.38-1.09]; univariate medians: 7.00 vs. 4.00 months). Analyses showed that each bevacizumab treatment group relative to non-bevacizumab had a reduced risk of death (bevacizumab-monotherapy regimen: HR 0.56 [95 % CI 0.31-1.03] and bevacizumab-combination regimen: HR 0.34 [95 % CI 0.21-0.68]). Patients receiving the bevacizumab-combination regimen trended toward longer OS and PFS than those receiving the bevacizumab-monotherapy regimen. Rates of bevacizumab-related toxicities were consistent with clinical trial reports.Journal of Neuro-Oncology 03/2015; DOI:10.1007/s11060-015-1752-y · 2.79 Impact Factor
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ABSTRACT: Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma.Oncotarget 02/2015; · 6.63 Impact Factor
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ABSTRACT: DNA hypermethylation is reported as a frequent event and prognostic marker in head and neck squamous cell carcinomas (HNSCC). Methylation has been commonly assessed with non-quantitative methodologies, such as methylation-specific PCR (MSP). We investigated previously reported hypermethylated genes with quantitative methodology in oral tongue squamous cell carcinomas (OTSCC). The methylation status of 12 genes in 115 OTSCC samples was assessed by one or more of three quantitative analyses: methylation sensitive high resolution melting (MS-HRM), sensitive-melting analysis after real time-methylation specific PCR (SMART-MSP), and bisulfite pyrosequencing. In contrast to much of the literature, either no or infrequent locus-specific methylation was identified by MS-HRM for DAPK1, RASSF1A, MGMT, MLH1, APC, CDH1, CDH13, BRCA1, ERCC1, and ATM. The most frequently methylated loci were RUNX3 (18/108 methylated) and ABO (22/107 methylated). Interrogation of the Cancer Genome Atlas (TCGA) HNSCC cohort confirmed the frequency of significant methylation for the loci investigated. Heterogeneous methylation of RUNX3 (18/108) and ABO (22/107) detected by MS-HRM, conferred significantly worse survival (P = 0.01, and P = 0.03). However, following quantification of methylation levels using pyrosequencing, only four tumors had significant quantities (>15%) of RUNX3 methylation which correlated with a worse patient outcome (P <0.001), while the prognostic significance of ABO hypermethylation was lost. RUNX3 methylation was not prognostic for the TCGA cohort (P = 0.76). We demonstrated the critical need for quantification of methylation levels and its impact on correlative analyses. In OTSCC, we found little evidence of significant or frequent hypermethylation of many loci reported to be commonly methylated. It is likely that previous reports have overestimated the frequency of significant methylation events as a consequence of the use of non-quantitative methodology.12/2014; 6(1):22. DOI:10.1186/1868-7083-6-22