MGMT promoter methylation level is a predictor of supermutation in LGG recurrence

Studies have found that some idh mutant low-level glioma (LGG) patients treated with Temodine (TMZ) develop super mutations on relapse and progress towards malignancy into high-level gliomas; MGMT code O6-methyl intenine-DNA methyl transferase is a DNA repair protein that removes TMZ-induced cytotoxicity and potential mutationTMZ can extend the survival of glioblastoma (GBM) patients, but its therapeutic effect on LGG is unclear and the potential risks associated with treatment need to be weighedRadhika Mathur of the University of California, San Francisco Neurosurgery and others found that epigenetic silencing of MGMT through promoter methylation helped TMZ cause LGG to change, leading to supermutations in relapse; lgG's MGMT promoter methylation levels could be used as a predictor of relapsesThe findings were published online in The March 2020 in Neuro-Oncologythe study method
the study used sulphate amplification sequencing (BSAS) to identify the MGMT promoter methylation status in 109 surgical tissue specimensBSAS combines the conversion of sulphate salsa in genomic DNA with polymerase chain reaction (PCR) in the target regionThe 109 specimens were from 37 original tumor specimens and relapsed specimens of LGG patients treated by TMZThe authors used methylation chips to verify the results of sequencing to assess the relationship between methylation and gene expression, and to determine the hypermutation state using exobiome sequencingThe MGMT boot sub-region identified by theauthors contains 273 bp areas of 27 CpG sites (chr10:129,467,210-129,467,482;hg38)This region spans the areas amplified by methylation-specific PCR (MSP)The MSP test area is a clinically determined area for MGMT methylationthe results of the studyfound that recurrent specimens of hypermutations usually showed an increase in methylation levels at cpG sites and were clustered separately from those not super-mutations on clustered heat mapsCompared to non-hypermutations, the level of mGMT gene expression was significantly reduced when the supermutation recursCompared with patients who did not have hypermutation at the time of recurrence, the methylation level of MGMT promoters in the initial tumor of patients with hypermutation stoicism at the time of recurrence was significantly increased (45.7%: 34.8% ;p s 0.027) Through the analysis of single-variable models and multivariate models including patient age and tumor molecular subtypes, it was found that the MGMT methylation level of the primary LGG could predict the hypermutation of recurrence conclusions the authors believe that the results of this study show that MGMT promoter methylation levels can be used as potential biomarkers, explaining the mechanism by which LGG is driven by TMZ to produce supermutations, and helping to detect MGMT promoter methylation levels and determine treatment measures in view of the risk of hypermutation severing when LGG recurs.