CYP1A1 Ile462Val Polymorphism Contributes to Lung Cancer Susceptibility among Lung Squamous Carcinoma and Smokers: A Meta-Analysis

Introduction

Lung cancer remains the most lethal cancer worldwide, despite improvements in diagnostic and therapeutic techniques [1]. Its incidence has been increasing in many parts of world, particularly in China, which has become a major public health challenge all the world [2]. The mechanism of lung carcinogenesis is not understood. Although cigarette smoking is the major cause of lung cancer, not all smokers develop lung cancer [3], which suggests that other causes such as genetic susceptibility might contribute to the variation in individual lung cancer risk [4], [5]. Many environmental carcinogens require metabolic activation by drug-metabolizing enzymes. In recent years, several common low-penetrance genes have been implicated as potential lung cancer susceptibility genes.

Cytochrome P450 1A1 (CYP1A1) metabolizes several suspected procarcinogens, particularly polycyclic aromatic hydrocarbons (PAHs), into highly reactive intermediates [6]. These compounds bind to DNA to form adducts, which, if unrepaired, can initiate or accelerate carcinogenesis. Although PAHs are ubiquitous in the environment, notable sources of exposure that cause the greatest concern include smoking, air pollution, diet, and certain occupations [7]. Two functionally important nonsynonymous polymorphisms have been described for the CYP1A1 gene, a base substitution at codon 462 in exon 7, resulting in substitution of isoleucine with valine (Ile462Val (exon 7)) (National Center for Biotechnology Information single nucleotide polymorphism(SNP) identifier rs1048943; adenine (A) to guanine (G) substitution at nucleotide 2455(2455A.G)) and a point mutation (thymine (T) to cytosine (C)) at the MspI site in the 3′-untranslated region (rs4646903;3801T.C) [8]. The Ile462Val (exon 7) restriction site polymorphism resulted in three genotypes: a predominant homozygous (Ile/Ile), the heterozygote (Ile/Val), and the rare homozygous (Val/Val).

An association between CYP1A1 polymorphisms and lung cancer was first reported by Kawajiri and co-workers in 1990 among an Asian study population [9], after which many studies analyzed the influence of CYP1A1 polymorphisms on lung cancer risk; no clear consensus, however, was reached. Moreover, 3 meta-analyses have reported conflicting results. Houlston RS [10] found no statistically significant association between the MspI polymorphism and lung cancer risk in 15 studies, in a meta-analysis performed by Le Marchand L et al. [11] included only 11 studies, the Ile462Val (exon 7) polymorphism did not correlate with lung cancer risk. Shi X [12], however, noted a greater risk of lung cancer for CYP1A1 MspI and exon 7 polymorphism carriers in a meta-analysis that included only Chinese population in 15 studies.

A single study might not be powered sufficiently to detect a small effect of the polymorphisms on lung cancer, particularly in relatively small sample sizes. Various types of study populations and study designs might also have contributed to these disparate findings. To clarify the effect of the CYP1A1 Ile462Val (exon 7) polymorphism on the risk for lung cancer, we performed an updated meta-analysis of all eligible case-control studies to date and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung caner and smoking status of case.

Materials and Methods

Results

Discussion

CYP genes are large families of endoplasmic and cytosolic enzymes that catalyze the activation and detoxification, respectively, of reactive electrophilic compounds, including many environmental carcinogens (e.g., benzo[a] pyrene). CYP1A1 is a phase I enzyme that regulates the metabolic activation of major classes of tobacco procarcinogens, such as aromatic amines and PAHs [6]. Thus, it might affect the metabolism of environmental carcinogens and alter the susceptibility to lung cancer. This meta-analysis explored the association between the CYP1A1 exon7 gene polymorphisms and lung cancer risk, and performed the subgroup analysis stratified by ethnicity, histological types of lung caner, gender and smoking status of case and control population. Our results indicated a significant association between CYP1A1 exon7 gene polymorphism and lung cancer risk Asians, Caucasians, lung SCC and Female population, no significant association was found in mixed population, lung AD, lung SCLC and Male population. Additionally, a significant association was found in smoker population and not in non-smoker populations.

When stratified according to ethnicity, a significantly increased risks were identified among Asians and Caucasians for the 2 exon 7 genotype variants, however no significant association was found in mixed population. These findings indicate that polymorphisms of CYP1A1 exon 7 polymorphism may be important in specific ethnicity of lung cancer patients. Population stratification is an area of concern, and can lead to spurious evidence for the association between the marker and disease, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they lived in [60]. In fact, the distribution of the less common Val allele of exon 7 genotype varies extensively between different races, with a prevalence of ∼25% among East Asians, ∼5% among Caucasians and ∼15% among other population. In addition, in our meta-analysis the between-study heterogeneity was existed in overall population, the subgroup of Asian and Caucasian for exon 7 genotypes. The I-squared value of Asian group is 57%, which is lower than the I-squared values for the Caucasians and mixed population studies, suggesting less heterogeneity among the Asian populations. Therefore, additional studies are warranted to further validate ethnic difference in the effect of this functional polymorphism on lung cancer risk.

There are growing biological and epidemiological data to suggest that different lung cancer pathological subtypes, particularly the two most common, are distinct etiological entities that should be analyzed separately [61]. When subgroup analyses by pathological types were considered, CYPIAl exon7 variant alleles were found to be associated with a 1.4 fold increase in the risk of lung SCC. However, for lung AC and SCLC, no significant association was found. Our findings were consistent with the Le Marchand L et al study [26] with largest sample sizes of case and control. Le Marchand et al. hypothesized that genetic susceptibility to PAHs predominantly caused lung SCC and nitrosamines caused lung AC. With introduction of filter-tipped cigarettes, probably decreased smokers’ exposure to PAHs and increased their exposure to nitrosamines, decreasing trend of SCC, relative to the increase in AC indirectly supports this hypothesis [62]. Different carcinogenic processes may be involved in the genesis of various tumor types because of the presence of functionally different CYP1Al exon7 gene polymorphisms. However, the possible molecular mechanisms to explain these histology-specific differences in the risk of lung cancer remain unresolved.

As we know, aside from genetic factor, smoking is the major risk factor of lung cancer. Most studies out of 40 studies reported information on smoking habits of cases and controls, however only ten eligible publications provided non-smokers information. Our meta-analysis results showed that a significantly increased risk was found to be associated with the CYP1A1 exon 7 gene polymorphisms and lung cancer risk in smokers, however, no significant association was found among non-smokers. The I-squared value of non-smokers groups is lower than the I-squared values for the smoker population studies, suggesting less heterogeneity among non-smokers populations. Tobacco smoke contains many of carcinogens and procarcinogens, such as benzopyrene and nitrosamine. These compounds are metabolized by the phase I enzymes including CYP family enzymes and converted to inactivemetabolites by the phase II enzymes. Our results should indicate the interaction between CYP1A1 exon 7 gene polymorphisms and smoking in the development of lung carcinoma. However, the association between the extent of smoke exposure and lung caner risk was not clear, further studies with larger sample size are needed to provide insights into the association.

Some limitations of this meta-analysis should be acknowledged. First, heterogeneity can interfere with the interpretation of the results of a meta-analysis. Although we minimized this likelihood by performing a careful search of published studies, using explicit criteria for a study’s inclusion and performing strict data extraction and analysis, significant interstudy heterogeneity nevertheless existed in nearly every comparison. The presence of heterogeneity can result from differences in the selection of controls, age distribution, and prevalence of lifestyle factors. Further, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings might be unpublished. Finally, in the subgroup analyses, different ethnicities were confused with other population, which may bring in some heterogeneity. As studies among the Indians and Africans are currently limited, further studies including a wider spectrum of subjects should be carried to investigate the role of these variants in different populations.

In conclusion, the results of our meta-analysis have provided the comprehensive and convincing evidence that CYP1A1 exon 7 polymorphisms are an important modifying factor in determining susceptibility to lung cancer. The effect of CYP1A1 exon 7 gene polymorphisms is diverse by the subgroup analysis stratified by ethnicity, histological types of lung caner and gender of case and control population. More importantly, our study confirms that there is an interaction between two genotypes of CYP1A1 exon 7 gene polymorphisms and smoking. For future studies, strict selection of patients, well-matched controls and larger sample size will be required. Moreover, gene–gene and gene–environment interactions should also be considered.

Funding Statement

The authors have no support or funding to report.