Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
DNA Repair (Amst). 2010 May 4;9(5):558-66. doi: 10.1016/j.dnarep.2010.02.006. Epub 2010 Mar 4.
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.
甲基化试剂参与致癌作用，而 DNA 修复蛋白 O(6)-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）可从 O(6)-甲基鸟嘌呤上去除甲基。已证明 DNA 修复基因的遗传变异可导致头颈部鳞状细胞癌（SCCHN）易感性增加。我们假设 MGMT 多态性与 SCCHN 风险相关。在一项基于医院的病例对照研究中，我们对 721 例 SCCHN 患者和 1234 例年龄、性别和种族相匹配的无癌对照进行了研究，对四个 MGMT 多态性（两个位于外显子 3，16195C>T 和 16286C>T，两个位于启动子区域，45996G>T 和 46346C>A）进行了基因分型。我们发现，这些多态性单独存在时均不会对 SCCHN 风险产生显著影响。但是，当通过潜在风险基因型的数量（即 16195CC、16286CC、45996GT+TT 和 46346CA+AA）对这四个多态性进行评估时，与零到两个风险基因型相比，具有三到四个风险基因型的患者发生 SCCHN 的风险显著增加（校正优势比（OR）=1.27；95%置信区间（CI）=1.05-1.53）。这种风险增加在年轻患者（OR=1.81；95%CI=1.11-2.96）、男性（OR=1.24；95%CI=1.00-1.55）、既往吸烟者（OR=1.25；95%CI=1.01-1.56）、既往饮酒者（OR=1.29；95%CI=1.04-1.60）、口咽癌患者（OR=1.45；95%CI=1.12-1.87）和伴有区域淋巴结转移的口咽癌患者（OR=1.52；95%CI=1.16-1.89）中更为明显。综上所述，我们的研究结果提示，MGMT 变异中的任何一种可能都不会对 SCCHN 风险产生实质性影响，但多个 MGMT 变异的联合作用可能会增加 SCCHN 的风险和进展，特别是在非西班牙裔白人的口咽癌中。
