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An intronic genetic variation of MGMT affects enhancer activity and is associated with glioma susceptibility

Authors Huang L, Xu W, Dai L, Yan D, Zhang S, Shi X

Received 8 June 2018

Accepted for publication 6 August 2018

Published 27 September 2018 Volume 2018:10 Pages 3995—4003

DOI https://doi.org/10.2147/CMAR.S176622

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Liming Huang,1 Wenshen Xu,2 Lian Dai,3 Danfang Yan,4 Shu Zhang,1 Xi Shi1

1The First Department of Chemotherapy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; 2Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; 3Department of Medicine, The Third Affiliated People’s Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China; 4Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Purpose: O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in repairing damaged DNA caused by alkylating agents. A number of cancer susceptibility loci have been recognized as enhancer variants. This study aimed to explore the significance of enhancer variants of MGMT in glioma susceptibility.
Patients and methods: A retrospective case-control study consisting of 150 glioma patients and 327 controls was conducted to test whether enhancer variants of MGMT are associated with glioma susceptibility. Genotypes were determined by Sequenom MassARRAY technology. Associations were estimated by logistic regression. Biochemical assays were used to examine the function of glioma susceptibility locus.
Results: We found that the A allele of rs10764901, an intronic variant of MGMT, was associated with a significantly decreased risk of glioma. The rs10764901 AA genotype carriers had an OR of 0.49 (95% CI, 0.24–0.98; P=0.045) compared with the rs10764901 GG genotype. When the rs10764901 AG and AA genotypes were pooled for analysis, a significantly decreased risk of glioma was also found (OR, 0.63; 95% CI, 0.43–0.93; P=0.021). Functional analyses showed that the rs10764901 A allele drove a lower luciferase expression and had higher transcription factor binding affinity than the G allele.
Conclusion: An enhancer variant of MGMT rs10764901 affects the regulatory activity of enhancer by altering the binding affinity of transcription factors and is associated with glioma susceptibility.

Keywords: glioma, MGMT, enhancer, genetic variation, susceptibility

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