Kihara M, Kihara M, Noda K
Department of Epidemiology, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
Carcinogenesis. 1995 Oct;16(10):2331-6. doi: 10.1093/carcin/16.10.2331.
Genes for cytochrome P4501A1 (CYP1A1) and glutathione S-transferase class mu (GSTM1) have been shown to be polymorphic, and have been implicated in tobacco-related carcinogenesis. In the present study, the role of the combined genotypes CYP1A1 and GSTM1 as a possible modulator of smoking related lung cancers was studied in relation to the tobacco smoke exposure level in 118 Japanese patients aged < 70 with squamous or small cell carcinomas of the lung. Among male smoking patients, the overall proportion of the GSTM1 null genotype (GSTM1[-]) was slightly higher than among healthy male smoker controls (56.7% versus 48.1%, P = 0.17). Little difference was observed between smoker patients and corresponding controls in overall frequencies of m2 mutant allele homozygotes (CYP1A1[m2/m2]) (16-18%) and Val encoding allele homozygotes (5-6%). However, when subjects were categorized by both CYP1A1 genotype (MspI polymorphism) and GSTM1 genotype, GSTM1(-) became markedly more expressed in patients with CYP1A1(m2/m2) when compared to the corresponding smoker controls (81.3% versus 39.4%, P < 0.01). When odds ratios were estimated using nonsmoking patients and healthy controls as a reference, the relative risk for developing lung cancer was found to increase in a cigarette dose-dependent manner across all combinations of genotypes. Furthermore, a 7- to 8-fold variation in risk was found among the various combinations; 3.2 in individuals with combined GSTM1(+) and CYP1A1(m2/m2) and 21.9 in those with combined GSTM1(-) and CYP1A1(m2/m2) genotype when the smoking index (sigma cigarettes smoked per day x years of smoking) was set at > or = 800. The results suggest that individuals having CYP1A1(m2/m2) are relatively resistant to tobacco-related lung cancers when combined with GSTM1(+), but are highly susceptible when combined with GSTM1(-). Combined CYP1A1 and GSTM1 genotype is thus a potential predictor of genetic susceptibility to smoking-related lung cancers in populations where CYP1A1 m2 or Val alleles are common.
细胞色素P4501A1（CYP1A1）基因和谷胱甘肽S-转移酶μ类（GSTM1）基因已被证明具有多态性，并与烟草相关的致癌作用有关。在本研究中，针对118名年龄小于70岁、患有肺鳞状细胞癌或小细胞癌的日本患者，研究了CYP1A1和GSTM1联合基因型作为吸烟相关肺癌可能的调节因子的作用，并与烟草烟雾暴露水平相关联。在男性吸烟患者中，GSTM1无效基因型（GSTM1[-]）的总体比例略高于健康男性吸烟者对照组（56.7%对48.1%，P = 0.17）。在吸烟患者和相应对照组之间，m2突变等位基因纯合子（CYP1A1[m2/m2]）（16 - 18%）和缬氨酸编码等位基因纯合子（5 - 6%）的总体频率差异不大。然而，当根据CYP1A1基因型（MspI多态性）和GSTM1基因型对受试者进行分类时，与相应的吸烟对照组相比，CYP1A1(m2/m2)患者中GSTM1(-)的表达明显更高（81.3%对39.4%，P < 0.01）。当以非吸烟患者和健康对照为参考估计比值比时，发现所有基因型组合中患肺癌的相对风险均以香烟剂量依赖的方式增加。此外，在不同组合中发现风险存在7至8倍的差异；当吸烟指数（每天吸烟支数×吸烟年数）设定为≥800时，GSTM1(+)和CYP1A1(m2/m2)组合的个体风险为3.2，而GSTM1(-)和CYP1A1(m2/m2)基因型组合的个体风险为21.9。结果表明，CYP1A1(m2/m2)个体与GSTM1(+)组合时对烟草相关肺癌具有相对抗性，但与GSTM1(-)组合时则高度易感。因此，在CYP1A1 m2或缬氨酸等位基因常见的人群中，CYP1A1和GSTM1联合基因型是吸烟相关肺癌遗传易感性的潜在预测指标。
