CYP450 polymorphisms as risk factors for early-onset lung cancer: gender-specific differences

Abstract

Cytochrome P450 (CYP) enzymes, involved in metabolism of tobacco carcinogens, are also involved in estrogen metabolism and many are regulated by estrogens. These genes may thus be of relevance to gender-specific differences in lung cancer risk, particularly in early-onset lung cancer, where a high proportion of women is observed. We conducted a case-control study to investigate genetic polymorphisms in cytochromes that might modify the risk of developing early-onset lung cancer. In total, 638 Caucasian patients under the age of 51 with primary lung cancer and 1300 cancer-free control individuals, matched by age and sex, were included in this analysis. Thirteen polymorphisms in the CYP1A1, CYP1B1, CYP2A13, CYP3A4 and CYP3A5 genes were analyzed. No significant association was found for any of the analyzed polymorphisms and lung cancer risk overall. However, among women, a significantly increased risk of early-onset lung cancer was observed for carriers of the minor allele of CYP1B1 SNP rs1056836 [odds ratio (OR) 1.97; 95% confidence interval (CI) 1.32-2.94; P < 0.001]. Also, a non-significant increase in lung cancer risk was observed in the group of women carriers of the minor allele of CYP2A13 SNP rs1709084 (OR 1.64; 95% CI 1.00-2.70; P = 0.05). The effect of these two polymorphisms was shown to be modified by smoking. Haplotype analysis was performed for CYP1B1 and CYP2A13. No differences between cases and controls were observed for both genes (P = 0.63 and P = 0.42 for CYP1B1 and CYP2A13, respectively). Our results suggest that the CYP1B1 and the CYP2A13 genotypes may contribute to individual susceptibility to early-onset lung cancer in women.

Association Between the CYP1B1 Polymorphisms and Lung Cancer Risk

“…Seven studies included enough information in a subgroup analysis by smoking status. 14,15,[18][19][20][21][22] The distribution of genotypes in the controls was consistent with Hardy-Weinberg equilibrium in all studies. All the cases were pathologically confirmed.…”

“…Several studies have studied the interaction or joint effect of CYP1B1 Leu432Val polymorphism and smoking status on lung cancer. 14,15,18,19,22 In the present meta-analysis, we found that CYP1B1 Leu432Val polymorphism had an increased lung cancer risk in smokers. It is possible that individuals with CYP1B1 Leu432Val polymorphism were more susceptible to smoking-related lung cancer when being exposed to higher level of tobacco smoke.…”

Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study

“…In addition to xenobiotic metabolism, CYP1B1 is also known to play a role in estrogen metabolism, and may contribute to differential susceptibility by sex toward smoking-related diseases. Genetic polymorphisms in CYP1B1 have been associated with an increased risk of lung cancer and early menopause in women; notably, interactions between singlenucleotide polymorphisms in CYP1B1 and smoking history appear to increase the risk of both of these outcomes (29)(30)(31). The differential correlations by sex between methylation at CYP1B1 and lung function and radiographic emphysema reported in our study warrant further investigation.…”

Association of CYP1B1 Leu432Val Polymorphism and Lung Cancer Risk: An Updated Meta-Analysis

“…There are two studies demonstrating a significantly increased risk of LC overall for carriers of the minor allele of CYP1B1 SNP rs1056836 among women and black ever-smoking women by Timofeeva et al [14] and Cote et al [15], respectively. However, other studies have failed to find any appreciable correlation between the CYP1B1 Leu432Val polymorphism and LC risk [16][17][18][19][20][21][22].…”