ABSTRACT
OBJECTIVES: To evaluate the prognostic values of microRNAs (miRNAs) in glioblastoma, and to see if there is an association between miRNAs and MGMT promoter methylation status. METHODS: We collected paraffin blocks from resection specimens from 114 glioblastoma patients who had received temozolomide treatment and radiotherapy. Real-time quantitative PCR was performed to determine the expression levels of five miRNAs. RESULTS: Upregulation of miR 125b-5p, miR 181d-3p, miR 221-3p, miR-222-3p, and miR 224-5p was observed in 13.2%, 5.3%, 12.3%, 32.5%, and 78.9% of the cases, respectively. The expression level of miRNAs was not significantly different in tumors with MGMT promoter methylation vs tumors without such methylation. Upregulation of miR 125b-5p, miR 181d-3p, or miR 221-3p was significantly associated with shorter survival in MGMT-unmethylated glioblastoma patients. CONCLUSIONS: miR 125b-5p, miR 181d-3p, and miR 221-3p are useful in predicting poor prognosis in patients with MGMT-unmethylated glioblastomas.
Subject(s)
Brain Neoplasms/diagnosis , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Glioblastoma/diagnosis , MicroRNAs/genetics , Tumor Suppressor Proteins/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , DNA Methylation , Gene Expression Regulation, Neoplastic/genetics , Glioblastoma/drug therapy , Glioblastoma/genetics , Humans , Male , Prognosis , Promoter Regions, Genetic/genetics , Survival Analysis , Temozolomide/therapeutic use , Up-RegulationABSTRACT
Promoter methylation is the most significant mechanism to regulate O6-methylguanine-DNA-methyltransferase (MGMT) expression. Single-nucleotide polymorphisms (SNPs) in the MGMT promoter region may also play a role. The aim of this study was to evaluate the clinical significance of SNPs in the MGMT promoter region of glioblastoma. Genomic DNAs from 118 glioblastomas were collected for polymerase chain reaction (PCR) amplification. Sanger sequencing was used to sequence the MGMT promoter region to detect SNPs. The results were correlated with MGMT status and patient survival. Rs1625649 was the only polymorphic SNP located at the MGMT promoter region in 37.5% of glioblastomas. Homozygous rs1625649 (AA genotype) was correlated with a higher MGMT methylation level and a lower protein expression, but the result was not statistically significant. In patients with MGMT methylated glioblastoma, cases with homozygous rs1625649 (AA genotype) were significantly associated with a lack of MGMT protein expression and a better progression-free survival (PFS) than the cases with wild type rs1625649 (CC genotype) or heterozygous rs1625649 (CA genotype). The survival impact was significant in multivariate analyses. In conclusion, the MGMT promoter homozygous rs1625649 (AA genotype) was found to correlate with a better PFS in patients with MGMT methylated glioblastoma.
