Expression of cytochrome P450 2A13 in human non-small cell lung cancer and its clinical significance

Lung cancer is one of the most important causes of cancer-related mortality worldwide. Human cytochrome P450 2A13 enzyme （CYP2A13） is predominantly expressed in the respiratory tract and could catalyze various carcinogens. In this study, we quantified CYP2A13 expression in non-small cell lung cancer （NSCLC） tissues and examined the relation between CYP2A13 and clinicopathologic factors. Thirty-five paired lung cancer and normal tissues were studied for the expression of the CYP2A13 gene by using real-time PCR and Western blot- ting assays. We also investigated the relationship between CYP2A13 expression and clinicopathologic factors such as age, gender, histology and lymph node status in tumor tissues. SPSS （17.0） statistical software was applied for data analysis. The real-time PCR results showed that there was no significant difference in the CYP2A13 mRNA transcript levels between tumor and paired normal tissues in the 35 samples and in 12 paired squamous cell car- cinomas. In adenocarcinoma, the expression of CYP2A13 mRNA in tumor tissues was 12.5% of that in adjacent tissues （P 〈 0.05） and it was not associated with age, gender, histology and lymph node status of the patients. The amounts of CYP2A13 proteins detected by Western blotting assays correlated well with those of the correspond- ing mRNAs. In conclusion, the expression of CYP2A13 was downregulated in lung adenocarcinoma. CYP2A13 may be involved in the development and progression of lung adenocarcinoma.

Different Effects of <i>TERT</i>, <i>TP</i>63, and <i>CYP</i>2<i>A</i>6 Polymorphism on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

Recent genome-wide association studies have identified lung cancer susceptibility loci, such as chromosome 5p15 (telomerase reverse transcriptase, TERT and cleft lip and palate transmembrane protein 1-like, CLPTM1L), 15q25 (nicotinic cholinergic receptor α, CHRNA3-CHRNA5), and 3q28 (tumor protein p63, TP63). Replication study was performed to confirm the association of the recently-identified susceptible loci (i.e., TERT-CLPTM1L, CHRNA3-CHRNA5, and TP63) in a total of 1460 male Japanese smokers (885 lung cancer cases and 575 healthy control subjects), which were previously studied for a low odds ratio of impaired or deletion polymorphism in cytochrome P450 2A6 (CYP2A6) for lung cancer risk. The minor allele frequency (0.442) of rs2736100 on 5p15 (TERT) was significantly higher in lung cancer cases than that (0.395) of controls, with an odds ratio of 1.27 (95% CI of 1.07 - 1.50, p = 0.00504). A series of subgroup analyses revealed the significant associations of rs4488809 (TP63, odds ratio of 1.21, p = 0.0422) and rs2736100 (TERT, odds ratio of 1.47, p = 6.40 × 10–5) with the risk of lung adenocarcinoma. No significant association of CHRNA3-CHRNA5 and CLPTM1L was found in this population. The present results support replication of the association of TERT and TP63 loci with lung adenocarcinomas and suggest subtype-specific effects of these loci on higher risk of lung cancer in smokers. The CYP2A6 including copy number polymorphism, uninvestigated in large-scale genome-wide association studies, may influence lower risk to heavy tobacco use-related lung cancer.

Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The current study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor allele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results support the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.