Matthias C, Bockmühl U, Jahnke V, Jones P W, Hayes J D, Alldersea J, Gilford J, Bailey L, Bath J, Worrall S F, Hand P, Fryer A A, Strange R C
Department of Otorhinolaryngology, Virchow-Klinikum, Humboldt-University, Berlin, Germany.
Pharmacogenetics. 1998 Apr;8(2):91-100.
Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.
谷胱甘肽S-转移酶GSTM1、GSTM3和GSTT1以及细胞色素P450 CYP2D6、CYP1A1和CYP2E1基因座是上呼吸消化道癌症的易感候选基因，因为在与酒精和烟草消费相关的其他疾病研究中已确定了可能具有保护作用和风险的基因型。我们描述了398例口腔、咽和喉鳞状细胞癌患者及219例对照个体的基因型频率。在假定具有保护作用的基因型中，只有GSTM1 A/B影响易感性；患者中GSTM1 A/B频率在年龄、性别、吸烟和饮酒量校正前低于对照个体[比值比=0.3，95%置信区间（CI）0.1 - 0.7]，校正后仍低于对照个体（比值比=0.2，95% CI 0.1 - 0.5）。在假定的风险基因型中，先前与皮肤癌易感性相关的GSTM3 AA在病例中频率较高（比值比=1.6，95% CI 1.1 - 2.4）。将病例分为口腔/咽和喉鳞状细胞癌后发现，喉鳞状细胞癌中GSTM3 AA频率高于对照个体（比值比=1.6，95% CI 1.1 - 2.5），对照个体与口腔/咽鳞状细胞癌之间的差异接近显著（比值比=1.7，95% CI 1.0 - 2.8）。假定具有保护作用的GSTM3 BB基因型在声门鳞状细胞癌患者（1.0%）中低于声门上鳞状细胞癌患者（3.0%）。我们未发现患者与对照个体在假定的风险基因型（如CYP2D6 EM、CYP1A1 m1/m1、CYP1A1 Ile/Ile、CYP2E1 DD、CYP2E1 c1c1、GSTT1无效）频率上存在差异，也未发现基因型与吸烟或饮酒之间的相互作用。我们得出结论，首先，μ类谷胱甘肽S-转移酶影响上呼吸消化道癌症风险，这补充了在皮肤癌患者中的研究结果，即GSTM1 A/B具有保护作用，而GSTM3 AA适度增加风险。GSTM1 A/B的影响，而非GSTM1 A或GSTM1 B（大多为GSTM1*0杂合子）表明两个表达的等位基因可能降低风险。虽然我们发现了GSTM3在喉纤毛中表达的免疫组化证据，但该多态性的生化后果尚不清楚。实际上，该基因的影响可能反映了与另一个基因的连锁不平衡。然而，我们未发现与GSTM1基因型存在关联。其次，我们得出结论，所研究的CYP2D6、CYP2E1、CYP1A1和GSTT1等位基因，尽管被认为是很好的候选基因，但要么不能决定上呼吸消化道中烟草衍生致癌物的解毒效果，要么是烟草和酒精的长期消费压倒了酶防御机制，而与基因型无关。
