In this study that investigated the role of polymorphic variants of glutathione S-transferase P1 (GSTP1) gene, it was found that there is a relationship between lung cancer and the exon 5 gene polymorphism genotype (p=0.037). Of exon 5 gene polymorphism frequencies, the frequency of allele A was found to be higher in the control group and allele G was found to be higher in the patients with lung cancer. Lung cancer risk was found to be 7.6 times higher in homozygote (GG) individuals than in those with AA genotype. When groups were evaluated in terms of exon 6 polymorphisms of the GSTP1 gene, no difference was observed between the groups.
Studies on tumor types reveal that the most common lung tumor is adenocarcinoma in women and squamous cell carcinoma in men [31,32]. In this study also, the rates of women with adenocarcinoma and men with squamous cell carcinoma were found to be high in the total population of patients. There are a lot of studies about GSTP1 exon 5 polymorphism in different populations. Nazar-Steward et al. , in their study on patients with lung cancer, found a connection between lung cancer risk and 105 val allele (G) and especially homozygote genotype (GG). Ryberg  found that patients with lung cancer had a higher homozygote allele G frequency compared to the control group. In this study which measured DNA adduct levels as well, they also found that adduct level in individuals with allele G (val) was higher compared to individuals with allele A (ile). In addition, they also determined that lung cancer risk was two-fold in homozygote individuals for allele G. To-Figueras et al.  determined no important difference between the patient and control groups in terms of allele frequencies in exon 5 polymorphism. Lin et al.  reported that lung cancer risk was high in those with squamous cell carcinoma who had mutant valine allele (G) in exon 5 of the gene GSTP1. Stucker et al. , in their study on 251 patients with lung cancer, determined a two-fold lung cancer risk increase in individuals with homozygote 105val (GG) genotype. Katoh et al.  studied this A→G polymorphism on the 313th nucleotide of GSTP1 in terms of its connection with various cancer types in the Japanese population but could not find any relationship with lung cancer. To-Figueras et al. , in their study on 164 North-West Mediterranean Caucasian patients with lung cancer, determined no difference between the patient and control groups in terms of allele frequencies in exon 5 polymorphism. Lewis et al. , in their study analyzing the relationship between lung cancer risk and GSTM1, GSTT1 and GSTP1 polymorphisms, determined that there wasn’t any connection between lung cancer risk and P1’s exon 5 genotypes. Kihara et al.  reported that exon 5 polymorphism of the gene GSTP1 did not change lung cancer risk by itself but the interaction of GSTP1 exon 5 genotypes with GSTM1 null genotype increased the risk.
Findings in some studies indicate that these polymorphisms on the gene GSTP1 do not affect the risk of lung cancer by themselves individually, but they can change the risk only if seen together with other genetic polymorphisms. Miller et al.  reported that in case of the combination of GSTP1 GG (105ile) + GSTM1 null or GSTP1 GG (105ile) + p53 Arg/Pro, Pro/Pro genotypes, this variant of GSTP1 influences the increase in lung cancer risk. Jourenkova et al.  determined that GSTP1 105 val allele has no connection with the increase in lung cancer risk by itself, however in combination with GSTM1 null and GSTM3 AA polymorphisms it contributes to increased risk.
The fact that the greatest factor in lung cancer is smoking shows the importance of various enzymes that play a role in the excretion through xenobiotic metabolism of toxic materials, such as PAH contained in the cigarette smoke. GSTP enzyme is an important one that catalyzes phase II reactions of this mechanism. The importance of GSTP enzyme in lung cancer, in addition to being the most expressed enzyme to the lungs, is being the most important enzyme that metabolizes activated products of benzo(a)pyren, a carcinogenic material contained in the cigarette smoke, such as BPDE. As a result of single nucleotide changes in this polymorphism in the GSTP1 gene, isoleucine aminoacid is synthesized at the 105th codon of GSTP1 gene’s exon 5 instead of alanine and this aminoacid change causes differences in the substrate binding active region of the enzyme. There are contradictions in most of the studies about the way this difference affects enzyme activity. Watson et al.  reported that individuals with the variant allele of exon 5 polymorphism have significantly lower GSTP enzyme activity. Sundberg et al.  argue that valine aminoacid synthesis in related regions in GSTP polypeptide due to the changes in GSTP1 gene’s exon 5 increases enzyme activity against BPDE, which is one of the major substrates of the enzyme and related to lung cancer because of its existence in the cigarette smoke, and thus aminoacid changes do not affect the risk for lung cancer. Contrary to this, Harries et al.  and Ryberg et al.  argue that valine variant has a low activity against polycyclic aromatic hydrocarbon diol epoxides, particularly against BPDE, and for this reason cancer risk will be higher in individuals with valine variant as detoxification potential will be lower. They have supported this argument with the finding that the frequency of valine variant is higher in patients with lung cancer compared to controls.
Our findings regarding the relationship between lung cancer and smoking, age and gender are consistent with the literature. It was determined in our study that GSTP1 exon 5 (ile105val) polymorphism is associated with the increase in lung cancer risk and the risk for lung cancer is about 7.5 times higher in individuals who have homozygote allele G. As a result of our evaluations taking into account the age, smoking habit, and tumor types of individuals; it is evident that the risk for lung cancer especially for adenocarcinoma is high in individuals who carry the mutant allele G of exon 5 of GSTP1 gene as homozygote. While adenocarcinoma is more prevalent in women, squamous cell carcinoma is more prevalent in men. The findings of our study parallels those of a major portion of literature about exon 5 polymorphism and its association with lung cancer. However, there is some literature arguing otherwise, stressing the effect of race in the relationship between these two polymorphisms and lung cancer. The findings regarding the effects of the GSTP1 polymorphisms on enzyme function and their relationship with lung cancer risk are contradicting. Therefore, more comprehensive studies evaluating the interaction of this polymorphism with genes related to lung cancer might prove useful in the future.
This study has been supported by Turkish Association for Cancer Research and Control, Terry Fox Research Grant.