CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women

Summary

Polymorphisms in metabolic genes encoding phase I and phase II enzymes are thought to modulate the risk of lung cancer via changes in enzymatic activity. Recently, the effect of these metabolic enzymes and their interaction with environmental factors has been studied in both smokers and also never-smokers, since never-smokers are a good model in which to study genetic susceptibility at low-dose carcinogen exposure.

Here, we investigated the association of CYP1A1 Ile462Val, CYP1B1 Leu432Val, GSTP1 Ile105Val, MPO G-463A polymorphisms and lung cancer risk in never-smoking Korean women. In this case–control study of 213 lung cancer patients and 213 age-matched healthy controls, we found that carrying one variant allele of the CYP1A1 Ile462Val polymorphism was associated with a significantly decreased risk of lung adenocarcinoma (adjusted odds ratio (OR) = 0.63; 95% confidence interval (CI), 0.41–0.99). Furthermore, the combination of risk genotypes of CYP1B1 Leu432Val with CYP1A1 Ile462Val was associated with the risk of lung adenocarcinoma (adjusted OR = 2.16; 95% CI, 1.02–4.57) as well as overall lung cancer (adjusted OR = 2.23; 95% CI 1.01–4.89). The polymorphisms of GSTP1 Ile105Val and MPO G-463A showed no significant association with lung cancer.

Theses results suggest that the CYP1A1 Ile462Val polymorphism is associated with a reduced risk of lung adenocarcinoma in never-smoking Korean women, whereas specific combinations of variant genotypes for metabolic enzymes increase lung cancer risk considerably.

Introduction

Lung cancer is the leading cause of cancer death in Korea as well as worldwide. Although cigarette smoking is the major risk factor for lung cancer in smokers, other risk factors that may play an important role in carcinogenesis in never-smoking lung cancer patients have not been fully established. Because genetic factors may have a significant effect on cancer development in cases of low-dose carcinogen exposure [1], [2], never-smokers are a good model in which to investigate genetic susceptibility to lung cancer. Individual susceptibility among never-smokers to lung cancer varies with the presence of single nucleotide polymorphisms in a variety of critical genes [3], [4]. Polymorphisms in metabolic enzymes, including phase I bioactivating enzymes and phase II detoxifying enzymes, have been studied to elucidate the association with the risk of lung cancer in never-smokers [5], [6], [7], [8].

CYP1A1 catalyzes the first oxidative step in the metabolism of polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) [9], [10]. Several epidemiological studies have shown the correlation between the risk of lung cancer and two well-known polymorphic variants of CYP1A1, CYP1A1 MspI and Cyp1A1 Ile462Val[11], [12], [13]. An analysis of a pooled population of Caucasian non-smokers revealed a significant correlation between CYP1Al gene polymorphisms and lung cancer [13], but a recent population-based study showed that neither CYP1A1 MspI nor CYP1A1 Ile462Val was associated with lung cancer susceptibility among Caucasians or African–Americans [6]. In non-smoking Chinese women, the Val/Val genotype of the CYP1A1 Ile462Val polymorphism increased lung cancer risk [8]. CYP1A1 variants also showed differential regulatory properties in the induction of expression and enzyme kinetics compared to the wildtype [14], [15], although some discrepancies remain among references. Schwarz et al. [16] reported a smaller enzyme activity of the CYP1A1 Ile462Val variant form when compared with the wildtype, but these results disagreed with those of Kawajiri et al. [17] who found a higher activity in the variant form.

CYP1B1 is another enzyme involved in the activation of carcinogens such as PAHs and arylamines to reactive metabolites that cause DNA damage [18]. Increased CYP1B1 expression has been reported in lung cancer patients, and it was suggested that the differential metabolizing activities of CYP1B1 variants were responsible for individual differences in cancer susceptibility [19], [20]. Another study showed that the CYP1B1 Leu432Val variant is associated with higher levels of DNA adducts within white blood cells [21], and a recent population-based study reported that CYP1B1 Leu432Val is strongly associated with increased lung cancer risk among non-smoking Caucasians [6]. However, the impact of the CYP1A1 and CYP1B1 polymorphisms on cancer risk may be modified when combined with other enzymes, such as glutathione S-transferase (GST) or myeloperoxidase (MPO) [6], [22].

In this study, we collected blood samples from never-smoking Korean women with lung cancer and age-matched, never-smoking, healthy control subjects. Using their DNA samples, we evaluated the association of lung cancer risk and four polymorphisms of CYP1A1, CYP1B1, GSTP1, and MPO in never-smokers. Furthermore, the influence of environmental tobacco smoke (ETS) and various combinations of genetic polymorphisms on lung cancer risk were also investigated.