An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma

Liming Huang,Pingping You,Danfang Yan,Xin You,Yuanyuan Ke,Xi Shi,Lian Dai,Jiaqi Xu,Wenshen Xu

doi:10.1186/s12935-021-02211-4

Abstract

BackgroundO6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated.MethodsThe associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case–control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown.ResultsWe found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39–0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40–0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27–0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35–0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21–0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population.ConclusionsThe study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.Graphic abstract

Highlights

O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage
Associations of the 4 tag-Expression quantitative trait loci (eQTLs) with MGMT expression levels were shown in Additional file 3
No evidence was found for the associations between the other 3 tag-eQTLs and glioma susceptibility (Table 1)

Summary

Introduction

O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. O6-methylguanine-DNA methyltransferase (MGMT) is a critical DNA repair enzyme which protects cells against the carcinogenic effects of alkylating agents. It repairs DNA alkylation damage by transferring the methyl moiety at O6 site of guanine onto its cysteine residues irreversibly. Upon this process, MGMT protein is consumed [5]. In glioma patients undergoing the alkylating agent temozolomide treatment, low MGMT expression was found to improve patient survival and treatment response, which may be due to the incomplete repair of temozolomide induced DNA alkylation damage in glioma cells [8]

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Conclusion