A novel analytical model of MGMT methylation pyrosequencing offers improved predictive performance in patients with gliomas

Abstract

The methylation status of the promoter of MGMT gene is a crucial factor influencing clinical decision-making in patients with gliomas. MGMT pyrosequencing results are often dichotomized by a cut-off value based on an average of several tested CpGs. However, this method frequently results in a "gray zone", representing a dilemma for physicians. We therefore propose a novel analytical model for MGMT methylation pyrosequencing. MGMT CpG heterogeneity was investigated in 213 glioma patients in two tested cohorts: cohort A in which CpGs 75-82 were tested and cohort B in which CpGs 72-78 were tested. The predictive performances of the novel and traditional averaging models were compared in 135 patients who received temozolomide using receiver operating characteristic curves and Kaplan-Meier curves, and in patients stratified according to isocitrate dehydrogenase gene mutation status. The results were validated in an independent cohort of 65 consecutive patients with high-grade gliomas from the Chinese Glioma Genome Atlas database. Heterogeneity of MGMT promoter CpG methylation level was observed in most gliomas. The optimal cut-off value for each individual CpG varied from 4-16%. The current analysis defined MGMT promoter methylation as occurring when at least three CpGs exceeded their respective cut-off values. This novel analysis could accurately predict the prognosis of patients in the methylation "gray zone" according to the standard averaging method, and improved the area under the curves from 0.67, 0.76, and 0.67 to 0.70, 0.84, and 0.72 in cohorts A, B, and the validation cohort, respectively, demonstrating superiority of this analytical method in all three cohorts. Furthermore, the advantages of the novel analysis were retained regardless of WHO grade and isocitrate dehydrogenase gene mutation status. In conclusion, this novel analytical model offers an improved clinical predictive performance for MGMT pyrosequencing results and is suitable for clinical use in patients with gliomas.

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

“…Recent advances in molecular studies, including the identification of the IDH mutation, 1p/19q co-deletion, H3 K27M mutation, EGFR amplification, TERT promoter mutation, BRAF V600E mutation, MGMT promoter methylation, and others, have revolutionized the diagnosis, classification, and precision chemotherapy of gliomas [5,8,9,14,19,24]. However, compared to brain gliomas, previous studies on spinal cord gliomas have usually included less than 30 cases in a single report, and the molecular characteristics of spinal cord glioma (astrocytoma) are still largely unknown [6,21,27,33,38].…”

Gene Expression Profiling Stratifies IDH-Wildtype Glioblastoma With Distinct Prognoses

“…Based on the median risk value (23,26), patients in CGGA-RNAseq, TCGA-RNAseq, and TCGA microarray databases were divided into high-and low-risk groups. Kaplan-Meier survival curves were calculated and the log rank tests were conducted to assess the prognostic significance (13,27). Differences in clinicopathologic features between the groups were determined using the Student's t-or Chi-square tests.…”

“…Given that IDH-wildtype and IDHmutant GBM are regarded as distinct entities despite their similar histology (11), further stratification of patients with IDH-mutant or IDH-wildtype GBM could be a promising approach for the diagnosis and treatment of GBM. The methylation status of the methylguanine methyltransferase (MGMT) promoter has been reported to have predictive value for both IDH-mutant and IDH-wildtype GBM (12,13). Our recent study presented a comprehensive somatic mutation landscape of secondary GBM and provided a protocol for MET-targeted therapy for precision neuro-oncology (14).…”

RNA processing genes characterize RNA splicing and further stratify lower-grade glioma

“…Although intensive treatment with surgery, radiotherapy, and chemotherapy are conducted, nearly all gliomas relapse. The median overall survival (OS) of patients with glioblastoma (GBM; WHO grade IV) is only approximately 15 months (1,3,4). Patients with lower-grade diffuse glioma (LGG, WHO grade II/III) have a relatively favorable prognosis, but these tumors evolve and most relapse as therapy-resistant higher-grade gliomas over time (5)(6)(7).…”