Division of Molecular Epidemiology, The Jikei University School of Medicine, Tokyo, Japan.
Real World Data Science Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
PLoS One. 2020 Apr 23;15(4):e0231932. doi: 10.1371/journal.pone.0231932. eCollection 2020.
Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC.
This study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC.
hmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026).
It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.
O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）DNA 修复酶通过启动子超甲基化（hmMGMT）的表观遗传沉默可能会增加抑癌基因 TP53 的突变，并促成致癌作用。本研究旨在探讨吸烟这一导致头颈部鳞状细胞癌（HNSCC）的危险因素是否会上调或下调 hmMGMT。此外，本研究还调查了 hmMGMT 和破坏性 TP53 突变对 HNSCC 患者复发的影响。
本研究纳入了 164 例 HNSCC 患者，这些患者均无 p16 蛋白表达和人乳头瘤病毒感染。采用多因素逻辑回归分析来研究吸烟与 hmMGMT 之间的关系。采用竞争风险回归分析来评估 hmMGMT 和外显子 2 到 11 中的 TP53 突变对 HNSCC 复发的影响。
在 164 例患者中，有 84%的患者存在 hmMGMT。在存在 hmMGMT 的患者中，特别是在 G:C>A:T 转换的 TP53 突变中，更常见（32%），而在不存在 hmMGMT 的患者中，TP53 突变更少见（8%）。两组间破坏性 TP53 突变的频率无显著差异。与非吸烟相比，20 包年或以上的重度吸烟与 hmMGMT 降低显著相关（校正比值比，0.08；95%CI，0.01 至 0.56；P=0.01）。同时存在 hmMGMT 和破坏性 TP53 突变的患者的复发率明显高于其他所有患者（亚分布危险比，1.77；95%CI，1.07 至 2.92；P=0.026）。
本研究发现，重度吸烟可抑制 hmMGMT，hmMGMT 与破坏性 TP53 突变相结合可能预示着 HNSCC 患者的预后不良。
