Abstract
BackgroundPolymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.MethodsgDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event.ResultsMost rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = − 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = − 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = − 0,450; p = 0.04) or CT (median = 137.80%; rho = − 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length.ConclusionrGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism.Trial registrationCONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.
Highlights
Polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene influence risk and overall survival of patients with brain tumor
Most recurrent glioblastoma (rGBM) patients showed global genomic DNA (gDNA) hypomethylation and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation compared to CC variant, which was not observed for CT variant. gDNA hypermethylated phenotype exhibited significant, moderate and negative correlations between TT genotype and gDNA hypermethylation levels when compared to CC or CT variants
Since gDNA methylation abnormalities are a hallmark of tumor progression [2], we proceeded to evaluate the impact of gDNA methylation status on the overall survival of patients undergoing perillyl alcohol (POH)-based treatment considering 25 weeks as survival time cutoff value
Summary
Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment. DNA methylation status, folate metabolism and its relevance for glioblastoma patients under perillyl alcohol (POH) inhaled therapy Similarities on global DNA methylation status among different tissues within the same individual indicate genetic influence on genomic DNA methylation status [1]. Genome-wide changes in DNA methylation pattern is a hallmark of cancer, glioblastoma (GBM) [2]. Epigenetic alteration in genomic DNA (gDNA) is a reversible and early event in malignant transformation, regulating gene expression and genomic stability [4]. Despite recent advances on neuroimaging and therapeutic approaches, time to tumor recurrence in GBM patients treated with surgery followed by chemo-radiotherapy is only 25 to 40 weeks, with a median overall survival around 14 months after diagnosis [9,10,11,12].following the emergence of drug-resistant clones, virtually all patients with GBM will suffer disease recurrence [13,14,15]
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