Interaction of susceptibility factors for the development of lung cancer

Cigarette smoking is the number one risk factor for lung cancer. However, only approximately 20% of smokers actually develop lung cancer. Therefore, additional factors such as host susceptibility must be involved with the cancer induction. Among the host factors, individual variations in the biotransformation of cigarette carcinogens due to the inheritance of variant versions of chemical metabolizing genes have been suspected to be the prime candidate. Therefore, the goal of my dissertation study is to elucidate the involvement of polymorphic metabolizing genes for the development of lung cancer. CYP2E1, MPO, GSTM1, GSTT1, and EH were chosen for analysis because they are known to metabolize chemicals that are present in cigarette smoke. The hypothesis is that inheritance of variant versions of these genes causes an increased body burden of reactive metabolites to induce chromosome aberrations (CA) and to increase the cancer risk. Molecular techniques were used to characterize the genes and to document the induction of CA. A group 167 lung cancer patients (LCP) and 150 smoking controls (SC) were studied.; The data indicates that LCP were more likely to carry the susceptibility EH exons 3 (EH3) and 4 (EH4) alleles than the controls. Compared to the wild-type gene, the EH3 heterozygous mutant allele reduced the risk (OR = 0.5; 95% CI 0.31–0.78) and the EH4 homozygous mutant allele increased the risk for LC (OR = 6.9; 95% CI 1.5–31.5). In addition, GSTM1 null genotype was associated with an increased risk to develop large cell carcinoma. Undifferentiated and combined types of cancer were associated with the susceptibility GSTM1, CYP2E1, or EH4 alleles. LCP who developed adenocarcinoma were more likely to carry the susceptibilty variants of EH3 or EH4 genes. The frequency of CA was significantly higher in LCP compared to SC (p < 0.001). Susceptibility variants of GSTM1, MPO and EH genes, significantly modulated the expression of CA among LCP.; This is the largest known study conducted that investigates the relationship between susceptibility metabolizing genes and CA induction as a mechanism for lung cancer. The results contribute to understanding the carcinogenic process and may lead to the development of cancer prevention programs.