PROGNOSTIC-SIGNIFICANCE OF GERM-LINE POLYMORPHISMS OF THE CYP1A1 AND GLUTATHIONE-S-TRANSFERASE GENES IN PATIENTS WITH NONSMALL CELL LUNG-CANCER

CYP1A1 is responsible for the metabolic activation of benzo(a)pyrene i n cigarette smoke, and high susceptibility to smoking-related lung can cer has been associated with the MspI polymorphism of the CYP1A1 gene. Individuals with a susceptible CYP1A1 genotype have been found to be at remarkably high risk when the genotype is combined with a deficient Mu-class glutathione 5-transferase (GSTM1) genotype. In this study, w e investigated the relationship between germ line polymorphisms of the se genes and clinical characteristics or survival rates in 232 patient s with non-small cell lung cancer (NSCLC). Statistical analysis reveal ed a significant association (P < 0.05) of the MspI polymorphism of th e CYP1A1 gene with histological type, performance status (general cond itions of patients), and the extent of the primary tumor (T-factor). O n the other hand, the GSTM1 polymorphism was significantly associated with performance status, the extent of regional lymph node metastasis (N-factor), and the extent of distant metastasis (M-factor), NSCLC pat ients with at least one susceptible allele of the MspI polymorphism of the CYP1A1 gene [heterozygous genotype B or a rare homozygous genotyp e C; n = 131; median survival time (MST) = 24.2 months] were associate d with a shortened survival compared with those with nonsusceptible ho mozygous alleles (genotype A; n = 101; MST = 65.2 months; P = 0.005 by log-rank test). Smokers with susceptible genotypes (n = 104; MST = 18 .2 months) were markedly associated with a shortened survival compared with those with genotype A (n = 76; MST = 69.2 months; P = 0.024); su ch an association was not found among nonsmokers by genotypes. Genotyp e-dependent survival was also observed in patients at an advanced stag e of disease (p = 0.010), but not in those at an early stage of diseas e (P = 0.382). Patients with the susceptible CYP1A1 genotype had remar kably shortened survivals when the genotype was combined with a defici ent genotype GSTM1(-) (P = 0.017; degree of freedom = 3). Multivariate analysis by the Cox proportional hazards model also revealed that the CYP1A1 polymorphism was an independent prognostic factor in patients at a nonresectable advanced stage of NSCLC (P = 0.005; hazard ratio = 1.98; 95% confidence interval, 1.24-3.17).