POLYMORPHISM IN CYTOCHROME-P450 CYP2D6, CYP1A1, CYP2E1 AND GLUTATHIONE-S-TRANSFERASE, GSTM1, GSTM3, GSTT1 AND SUSCEPTIBILITY TO TOBACCO-RELATED CANCERS - STUDIES IN UPPER AERODIGESTIVE TRACT CANCERS

Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 C YP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancer s of the upper aerodigestive tract because putatively protective and r isk genotypes have been identified from studies in other diseases asso ciated with alcohol and tobacco consumption. We describe genotype freq uencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 213 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSM1 A/B fre quency was lower in the patients than the control individuals both bef ore [adds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumptio n (odds ratio 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, wa s higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cas es into oral/pharyngeal and laryngeal squamous cell carcinoma showed t he 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 di fference 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 BE genotype was lower in patients wit h 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, CYP7A1 m1/ m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2B1 c1c1, GSTT1 null) or, interactio ns between genotypes and smoking or alcohol consumption. We: conclude, first, that mu class glutathione S-transferase influence risk of uppe r aerodigestive tract cancers thereby complementing studies in skin ca ncer patients showing GSTM1 A/B is protective, while GSTM3 AA moderate ly increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM 1 B (mostly heterozygotes with GSTM10) suggests that two expressed al leles may attenuate risk, While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical co nsequences of the polymorphism are unclear. indeed, the influence of t he gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we concl ude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, althoug h putatively good candidates, either do not determine the effectivenes s of detoxification of tobacco-derived carcinogens in the upper aerodi gestive tract or, that chronic consumption of tobacco and alcohol over whelms enzyme defences, irrespective of genotype. Pharmacogenetics 8: 91-100. (C) 1998 Lippincott-Raven Publishers.