Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma

Objective:O6 methylguanine-DNA methyltransferase(MGMT)promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy.Given that the IDH status has critical effects on the survival and epigenetic features of glioblastoma,we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma.Methods:This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison.KaplanMeier curves and multivariate Cox regression were used to study the predictive effects.Results:Compared with IDH-wildtype glioblastomas,IDH-mutant glioblastomas showed significantly higher(P<0.0001)MGMT promoter methylation.We demonstrated that MGMT promoter methylation status,as determined by a high cutoff value(≥30%)in pyrosequencing,could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy(cohort A);this result was validated in another cohort of 25 IDH-mutant glioblastomas(cohort B).The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases,and 18.37 and 41.61 months for methylated cases,and in cohort B were 6.97 and 9.10 months for unmethylated cases,and 23.40 and 26.40 months for methylated cases.In addition,we confirmed that the MGMT promoter methylation was significantly(P=0.0001)correlated with longer OS in IDH-mutant patients with GBM,independently of age,gender distribution,tumor type(primary or recurrent/secondary),and the extent of resection.Conclusions:MGMT promoter methylation has predictive value in IDH-mutant glioblastoma,but its cutoff value should be higher than that for IDH-wildtype glioblastoma.

Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer

Ribonucleotide reductase M2(RRM2)is a small subunit in ribonucleotide reduc-tases,which participate in nucleotide metabolism and catalyze the conversion of nucleotides to deoxynucleotides,maintaining the dNTP pools for DNA biosynthesis,repair,and replication.RRM2 performs a critical role in the malignant biological behaviors of cancers.The structure,regulation,and function of RRM2 and its inhibitors were discussed.RRM2 gene can produce two transcripts encoding the same ORF.RRM2 expression is regulated at multiple levels during the processes from transcription to translation.Moreover,this gene is associated with resistance,regulated cell death,and tumor immunity.In order to develop and design inhibitors of RRM2,appropriate strategies can be adopted based on different mechanisms.Thus,a greater appreciation of the characteristics of RRM2 is a benefit for understanding tumorigenesis,resistance in cancer,and tumor microenvironment.Moreover,RRM2-targeted therapy will be more attention in future therapeutic approaches for enhancement of treatment effects and amelioration of the dismal prognosis.