MGMT Leu84Phe Polymorphism Contributes to Cancer Susceptibility: Evidence from 44 Case-Control Studies

Abstract

BackgroundO6-methylguanine-DNA methyltransferase is one of the few proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. A large number of case-control studies have been conducted to explore the association between MGMT Leu84Phe polymorphism and cancer risk. However, the results were not consistent.MethodsWe carried out a meta-analysis of 44 case-control studies to clarify the association between the Leu84Phe polymorphism and cancer risk.ResultsOverall, significant association of the T allele with cancer susceptibility was verified with meta-analysis under a recessive genetic model (P<0.001, OR=1.30, 95%CI 1.24-1.50) and TT versus CC comparison (P=0.001, OR=1.29, 95% CI 1.12-1.50). In subgroup analysis, a significant increased risk was found for lung cancer (TT versus CC, P=0.027, OR=1.67, 95% CI 1.06-2.63; recessive genetic model, P=0.32, OR=1.64, 95% CI 1.04-2.58), whereas risk of colorectal cancer was significantly low under a dominant genetic model (P=0.019, OR=0.84, 95% CI 0.72-0.97). Additionally, a significant association between TT genetic model and total cancer risk was found in the Caucasian population (TT versus CC, P=0.014, OR=1.29, 95% CI 1.05-1.59; recessive genetic model, P=0.009, OR=1.31, 95% CI 1.07-1.61), but not in the Asian population. An increased risk for lung cancer was also verified in the Caucasian population (TT versus CC, P=0.035, OR=1.62, 95% CI 1.04-2.53; recessive genetic model, P=0.048, OR=1.57, 95% CI 1.01-2.45).ConclusionsThese results suggest that MGMT Leu84Phe polymorphism might contribute to the susceptibility of certain cancers.

The potential role of MGMT rs12917 polymorphism in cancer risk: an updated pooling analysis with 21010 cases and 34018 controls

“…Finally, we enrolled another ten case–control studies [ 4 , 21 , 25 , 29 , 30 , 35 , 36 , 42 , 45 , 48 ]. In addition, when compared with another meta-analysis of Liu et al (2013) [ 13 ], which consisted of 44 case–control studies from 37 articles [ 4 , 5 , 16 , 17 , 19 , 20 , 22 , 23 , 25–27 , 31–33 , 35 , 37 , 38 , 42 , 43 , 45–47 , 49 , 51 , 52 , 54–63 , 65 , 66 ], we excluded four studies that were not in HWE [ 61–63 , 66 ], one that did not analyze colorectal cancer [ 60 ], and one that included other genetic variants [ 65 ]. We also added another 15 new case–control studies [ 18 , 21 , 24 , 28–30 , 34 , 36 , 39–41 , 44 , 48 , 50 , 53 ] for the analysis.…”

Deletion of the MGMT gene in familial melanoma

“…The four SNPs found in our material have previously been found in healthy controls and were not segregating with the disease. The polymorphisms are believed to be nonfunctional changes (Egyhazi et al, ; Pegg et al, ; Gu et al, ; Loh et al, ), although some studies have suggested the T allele variant of the Leu84Phe polymorphism is associated with increased cancer susceptibility (Du et al, ; Liu et al, ).…”

“…From the sequence analysis of the remaining 63 families, we found four MGMT SNPs. These SNPs are predominantly described as nonfunctional, but some researchers claim that the T‐allele variant of the Leu84Phe polymorphism is associated with increased cancer susceptibility (Du et al, ; Liu et al, ).…”

The PTPN13 Y2081D (T>G) (rs989902) polymorphism is associated with an increased risk of sporadic colorectal cancer

“…the interleukin‐1B (IL‐1B) and IL‐10 polymorphisms in gastric cancers and MGMT Leu84Phe in CRCs. This phenomenon is referred to as ‘allele flip’ and has been attributed to a range of mechanisms including differences in interactions between various SNPs or to general differences in both the genetic background and environment .…”