Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Abstract

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes -in subjects carrying simultaneously deviations from the common genotype in more than one gene -were overrepresented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers. Abstract. Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes -in subjects carrying simultaneously deviations from the common genotype in more than one gene -were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations o...

Correlation of CYP1A1, GSTP1 and GSTM1 gene polymorphisms and lung cancer risk among smokers

“…Smokers with CYP1A1 MspI variant/GSTM1-null genotypes were found to have increased levels of DNA adducts in lung tissue and leucocytes (17). Furthermore, in a Greek study by Dialyna et al the combination of rare variants of the CYP1A1, GSTM1 and GSTT1 genes was over-represented in lung cancer patients, compared to the control population and was significantly associated with a history of heavy tobacco consumption in lung cancer patients (23). In our study, consistent with previous studies, the combination of the MspI variant and GSTM1 deletion was significantly associated with lung cancer risk (p=0.029).…”

Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population

“…There was a trend of 4.4-fold increased relative risk for the GSTM1 null, GSTT1 null, CYP1A1 wild genotype combination (OR=4.401, 95% CI: 0.819-23.662) and a 3.5-fold increased risk, although not statistically significant (OR=3.747, 95% CI: 0.824-17.038), in individuals possessing the GSTM1 null, GSTT1 null, CYP1A1 variant genotype combination. A similar combination association of similar combination genotypes with lung cancer has been reported previously (Dialyna et al 2003). Due to gene-environment interactions, the effects of inheritance at independent loci can be additive, and each locus contributes incrementally to cancer development or epistasis in which inheritance at multiple loci is required to develop lung cancer.…”

Association of periodontitis with GSTM1/GSTT1-null variants—A pilot study

“…In particular, enzymes of classes μ (GSTM1) and τ (GSTT1), involved in the detoxification of polycyclic aromatic hydrocarbons (such as epoxides and hydroxylated metabolites of benzo-a-pyrene), present in tobacco smoke, seem to be the most important ones for the detoxification processes in the mucosa of the upper aerodigestive tract [17]. Associations between these polymorphisms and different types of cancer (such as the breast, lung, laryngeal, oral or oropharyngeal cancer) remain controversial [18][19][20][21][22]. Furthermore, the homozygous null GSTM1 and CYP1A1Val/Val genotype has been reported to be a strong risk factor for cancer only in smokers, suggesting a fundamental role for gene-environment interactions [23].…”