Polymorphisms of the DNA repair gene MGMT and risk and progression of head and neck cancer

Abstract

Methylating agents are involved in carcinogenesis, and the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) removes methyl group from O(6)-methylguanine. Genetic variation in DNA repair genes has been shown to contribute to susceptibility to squamous cell carcinoma of the head and neck (SCCHN). We hypothesize that MGMT polymorphisms are associated with risk of SCCHN. In a hospital-based case-control study of 721 patients with SCCHN and 1234 cancer-free controls frequency-matched by age, sex and ethnicity, we genotyped four MGMT polymorphisms, two in exon 3, 16195C>T and 16286C>T and two in the promoter region, 45996G>T and 46346C>A. We found that none of these polymorphisms alone had a significant effect on risk of SCCHN. However, when these four polymorphisms were evaluated together by the number of putative risk genotypes (i.e. 16195CC, 16286CC, 45996GT+TT, and 46346CA+AA), a statistically significantly increased risk of SCCHN was associated with the combined genotypes with three to four risk genotypes, compared with those with zero to two risk genotypes (adjusted odds ratio (OR)=1.27; 95% confidence interval (CI)=1.05-1.53). This increased risk was also more pronounced among young subjects (OR=1.81; 95% CI=1.11-2.96), men (OR=1.24; 95% CI=1.00-1.55), ever smokers (OR=1.25; 95%=1.01-1.56), ever drinkers (OR=1.29; 95% CI=1.04-1.60), patients with oropharyngeal cancer (OR=1.45; 95% CI=1.12-1.87), and oropharyngeal cancer with regional lymph node metastasis (OR=1.52; 95% CI=1.16-1.89). In conclusion, our results suggest that any one of MGMT variants may not have a substantial effect on SCCHN risk, but a joint effect of several MGMT variants may contribute to risk and progression of SCCHN, particularly for oropharyngeal cancer, in non-Hispanic whites.

Fig 1

Direct sequencing results for the MGMT -135G>T (GG, GT and TT) and -485C>A (CC, CA and AA)

Fig. 2

Linkage disequilibrium (LD) display for the four MGMT variants. A, the D’ display and B, the R² display, both showed that rs1803965 (Leu53Leu53) and rs12917 (Leu84Phe) are in LD with a D’ = 0.93 and R² = 0.78

Fig. 3

Meta-analysis of associations between the functional MGMT Leu84Phe (rs12917) variant and risk of SCCHN. The result of our overall risk estimate for SCCHN, the largest US study (Zhang 2009), was similar to that of another US study (Huang 2005) and a Tailand study (Kietthuthew 2006) but somewhat different from that of an European study (Hall 2007). Overall, this single variant was not associated with risk of SCCHN.