|Year : 2015 | Volume
| Issue : 4 | Page : 760-764
Association between CYP1A1 2454A > G polymorphism and colorectal cancer risk: A meta-analysis
Liang Xu, Hongwei Wei
Department of Oncology, General Hospital of Liaohe Oil Field, Xinglongtai, Panjin City 124010, Liaoning Province, China
|Date of Web Publication||15-Feb-2016|
Department of Oncology, General Hospital of Liaohe Oil Field, 26 Ying Bin Street, Xinglongtai, Panjin City 124010, Liaoning Province
Source of Support: None, Conflict of Interest: None
Background: The aim of our study was to assess the association of CYP1A1 2454A > G polymorphism and colorectal cancer (CRC) risk.
Materials and Methods: Electronic databases, including PubMed, MEDLINE Springer, Elsevier Science Direct, Cochrane Library, and Google Scholar were searched for relevant trials until December 2013. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analyses were conducted based on geographical region and size of the study samples.
Results: Thirteen eligible studies were included in this meta-analysis with 3490 cases and 4076 controls. There were significant associations under the overall ORs for G-allele comparison (G vs. A, pooled OR 1.29, 95% CI 1.03-1.61, P = 0.03), GG versus AA comparison (pooled OR 1.50, 95% CI 1.17-1.91, P < 0.01), recessive model (GG vs. GA + AA, pooled OR 1.52, 95% CI 1.20-1.94, P < 0.01) between CYP1A1 2454A > G polymorphism and CRC risk. Subgroup analyses stratified by geographical region demonstrated an association in Asia and Europe, but not in America.
Conclusion : This meta-analysis suggests that CYP1A1 2454A > G polymorphism might be associated with susceptibility of CRC and the allele G might increase the CRC risk in Asia and Europe.
Keywords: Colorectal cancer, CYP1A1 2454A > G, meta-analysis, polymorphism
|How to cite this article:|
Xu L, Wei H. Association between CYP1A1 2454A > G polymorphism and colorectal cancer risk: A meta-analysis. J Can Res Ther 2015;11:760-4
| > Introduction|| |
Colorectal cancer (CRC) is one of the common causes of cancer morbidity and mortality worldwide. , CRC is a multifactorial disease, and the underlying etiological factors and pathogenetic mechanisms of CRC appear to be complex and heterogeneous.  It was indicated that susceptibility to cancer was mediated by both environment and genetic factors. Exposure to environmental toxins is an important contributing factor. However, cancer risk may vary according to the individual's ability to clear the xenobiotics. 
The metabolism of xenobiotics like polycyclic aromatic hydrocarbons (PAHs), involves both activation (phase I) and detoxification (phase II) reaction by enzymes including cytochrome P450 group (CYPs), microsomal epoxide hydrolase group (EPHX), and glutathione-S-transferase group. , CYP1A1 is the phase I enzyme, which is an important member of the CYP family. CYP1A1 is involved in the metabolism of a large number of endogenous and exogenous procarcinogens including PAHs.  Genetic polymorphisms in CYP1A1 gene were thought to lead to greater carcinogen susceptibility and might alter the susceptibility to CRC. Several polymorphisms in this gene have been shown to affect the expression and activity of protein products.  One of them is A to G change at position 2454 in exon 7 which results in an isoleucine to valine substitution (rs1048943), correlates with increased enzymatic activity.  There were large numbers of epidemiologic studies performed in different ethnic populations regarding the association of CYP1A1 2454A > G polymorphism with CRC risk, but their results were contradictory. An increased CRC risk associated with CYP1A1 was observed in a number of studies, , but the unrelated relationship was found in other studies. , Therefore, we performed this meta-analysis to investigate whether polymorphism of CYP1A1 was associated with CRC.
| > Materials and methods|| |
Source of material and search method
Eligible studies were identified by a systematic literature search of PubMed, Springer, Elsevier Science Direct, Cochrane Library, Google Scholar, MEDLINE, and EMBASE up to December 2013. The following keywords were used for searching: "CYP1A1" or "2454A >G" or "rs1048943" and "CRC" or "colorectal carcinoma" and "polymorphism" or "variants" and "study" or "trial." Meanwhile, the references lists of retrieved articles were checked to find additional eligible studies.
Included and excluded standards of studies
Studies were included if they meeting the following criteria: (1) Case-control studies associated with CRC patients and healthy controls; (2) studies in which the participants were human beings; (3) studies that evaluated the association of CYP1A1 2454A > G polymorphism and CRC risk; (4) studies in which genotype distribution of CYP1A1 should be available for estimating the odds ratios (ORs); (5) Articles published in English; (6) studies in which control groups were in Hardy-Weinberg equilibrium (HWE).
The major exclusion criteria were as follows: (1) The design of studies was based on family or sibling pairs; (2) studies did not report the genotype frequencies; (3) studies did not evaluate the association of CYP1A1 2454A > G polymorphism and CRC susceptibility; (4) studies did not provide sufficient information for extraction; (5) studies just provided abstracts from meetings or conferences.
Study selection and extraction of data
Two investigators independently evaluated studies for their content. Initial screening was done by reading the titles and abstracts, followed by reading the full text of articles to determine the final inclusion. Discrepancies were resolved by discussion.
The following information was collected from each study: Study details (e.g., the first author's name, research year of study, year of publication, geographic region, study design, criteria for CRC, etc.), characteristics of participants (e.g., age, sample size, genotyping methods, and source of control group, etc.). Two investigators extracted the data independently using the standard data collection form, and a discussion was conducted among the authors to resolve any discrepancies. Authors would be contacted for clarification of any of the above-extracted data items if needed.
We used the STATA software package v. 11.0 (Stata Corporation, College Station, TX, USA) to pool results from the individual studies. HWE in the controls was assessed among the controls using a Chi-square test of goodness of fit, and a P < 0.05 was considered as significant disequilibrium. ORs and 95% confidence intervals (95% CIs) were used to assess the strength of association between CYP1A1 2454A > G polymorphism and CRC risk. The pooled ORs were calculated for G-allele comparison (G vs. A), co-dominant model (GG vs. AA, GA vs. AA), recessive model (GG vs. GA + AA), and dominant model (GG + GA vs. AA), respectively. The significance of pooled ORs was determined by Z-test and P <</i> 0.05 was considered as statistically significant. We assessed the within- and between-study variation or heterogeneity using the Chi-square-based Q-statistic test.  Moreover, the effect of heterogeneity was further quantified using the I2 test.  A P < 0.10 or I2 > 50% indicated that heterogeneity among studies existed, and then the random effect model (DerSimonian-Laird method  ) would be used for meta-analysis. Otherwise, the fixed effect model (Mantel-Haenszel method  ) would be used.
Evaluation of publication bias
Publication bias was evaluated using the Egger's linear regression test,  which measures funnel plot asymmetry on the natural logarithm scale of OR.
| > Results|| |
Characteristics of eligible studies
The process of study selection was presented in [Figure 1]. There were 1171 potentially relevant papers (311 from PubMed, 156 from MEDLINE, 192 from Springer, 107 from Elsevier Science Direct, 15 from Cochrane Library, 390 from Google Scholar). After removing duplicates or irrelevant studies, 102 articles were further reviewed. Then, 61 articles were excluded after screening the abstracts (32 were review articles; 29 not reported CYP1A1 gene). After that, 41 articles were full reviewed, and 28 articles were excluded (17 not reported CRC data; 11 provided no available data). Finally, 13 studies ,,,,,,,,,,,, met the inclusion criteria were included in our meta-analysis.
[Table 1] and [Table 2] show the characteristics of the included studies. The 13 selected studies contained 7566 participants, including 3490 cases and 4076 controls. The sample size of included studies ranged from 90 to 1463, which had been conducted in Europe, America, and Asia. Studies were all designed as case-control studies, and the source of control groups were subjects with no prior diagnosis of CRC or healthy subjects. The CYP1A1 2454A > G genotype frequencies in controls were in HWE in all included studies.
|Table 2: Genotype frequencies of CYP1A1 2454A > G polymorphism in studies included in the meta-analysis |
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Meta-analysis of the association between CYP1A1 2454A > G polymorphism and colorectal cancer risk
There was significant heterogeneity in CYP1A1 2454A > G among the included studies for G versus A allele, (P <</i> 0.1 and I 2 =77.3%), GA versus AA genotype (P <</i> 0.1 and I 2 =84.8%), and GG + GA versus AA genotype (P <</i> 0.1 and I 2 =84.3%). A summary of the meta-analysis findings of the association between CYP1A1 2454A > G polymorphism and susceptibility to CRC was shown in [Table 3]. No significant heterogeneity was found for GG versus AA genotype. Therefore, the random effects model were selected to merge data for G versus A allele, GA versus AA genotype, and GG + GA versus AA genotype, and the fixed effect model were chosen for pooling GG versus AA genotype and GG versus GA + AA genotype. Significant associations were found between CYP1A1 2454A > G polymorphism and CRC risk under G versus A allele, GG versus AA genotype, GG versus GA + AA genotype. However, no significant associations were found GA versus AA genotype and dominant model (GG + GA vs. AA, OR = 1.34, 95% CI = 0.98-1.83, P > 0.05).
|Table 3: Meta-analysis of the association between CYP1A1 2454A > G polymorphism and CRC in fixed/random effect model |
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In the subgroup analyses stratified by geographic location, it was showed that the CYP1A1 2454A > G polymorphism was significantly related with CRC risk in Europe (G vs. A: OR = 1.35, 95% CI = 1.10-1.67, P < 0.05; GA vs. AA: OR = 1.32, 95% CI = 1.05-1.65, P = 0.02; GG + GA vs. AA: OR = 1.35, 95% CI = 1.08-1.69, P < 0.01), America (GG vs. AA: OR = 2.98, 95% CI = 1.07-8.32, P = 0.04), and Asia (GG vs. AA: OR = 1.38, 95% CI = 1.07-1.79, P = 0.01; GG vs. GA + AA: OR = 1.44, 95% CI = 1.12-1.86, P < 0.01). Subgroup analyses stratified according to the sample size showed the results were not changed when studies with sample size <500 were compared with studies with sample size ≥500.
The Egger's test was performed to assess the publication bias. No publication bias was found among the included studies (P > 0.05). The detailed data were present in [Table 4].
|Table 4: Tests for publication bias (Egger's test) in population (overall) |
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| > Discussion|| |
Various attempts had been made to summarize existing studies investigating the association of CYP1A1 2454A > G polymorphism with CRC risk in recent years. Our results indicated that CYP1A1 2454A > G polymorphism might be associated with susceptibility of CRC, and the allele G might increase the CRC risk in Asia and Europe.
The results of the present study were consistent with other two previous meta-analyses conducted by Jin et al.  and Zheng et al.,  respectively. However, our meta-analysis performed better than previous two studies in two aspects. First, only studies in which genotype distributions were in HWE were included in our meta-analysis. Second, apart from subgroup analysis based on region distribution, we additionally applied stratified analysis by sample sizes to investigate potential sources of heterogeneity. No reversed results were found between studies with sample size ≥500 and studies with sample size <500. The inconsistent conclusions of subgroup analyses according to region distribution suggest that the high heterogeneity among all the enrolled studies might be introduced by region distribution. Moreover, the high heterogeneity in the USA subgroup analysis demonstrated that heterogeneity occurred between the two enrolled studies conducted in the USA.
From the subgroup analysis of geographical regions, we found that the CYP1A1 2454A > G polymorphism might be associated with CRC risk in Asia and Europe, but not in America. There are many factors influencing the strength of the conclusion. First, the different distribution of G allele between different geographical regions might be account for the different conclusion. , Second, the sample size in studies conducted in America was small. There were only 369 cases in America, compared with 1658 and 1463 cases in Asia and Europe, respectively. Third, significant heterogeneity was still observed in some comparisons of the America subgroup but not in Asia and Europe subgroups. This may distort the result. Moreover, it was possible that different CRC risks in different populations were due to exposure to various environmental factors, for its multifactor (both genetic and environmental factors) features.
Over the past years, a number of critical mutations underlying the pathogenesis of the sporadic have been revealed.  CYP1A1 is a key phase I enzyme that converts xenobiotics and a small number of endogenous substrates into reactive and toxic intermediates. Due to the presence of mutant variant at position 2454, the activity of CYP1A1 enzyme would be enhanced.  Individuals with higher CYP1A1 activity could be at increased risk of development of CRC when the gene was exposed to several environmental toxins such as PAHs and other xenobiotics. Meanwhile, previous studies have indicated a significant association between CYP1A1 and other cancers such as lung cancer  and esophageal cancer  with a similar mechanism.
This study still has some limitations that should be acknowledged. First, only published studies were included in the present meta-analysis. Unpublished studies and abstracts from conferences were not included in our study. Thus, publication bias may occur even though it was not found by making use of a statistical test. In addition, there still need more and high-quality case-control studies to test and verify the results of this meta-analysis because recruited studies were case-control study and the numbers of studies were small.
The meta-analysis suggests that CYP1A1 2454A > G might be associated with susceptibility of CRC, and the allele G might increase the CRC risk in Asia. Well-designed studies with larger sample size based on different populations are needed to confirm our results.
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[Table 1], [Table 2], [Table 3], [Table 4]