Relationships Between CYP1A1 Genetic Polymorphisms and Bladder Cancer Risk: A Meta-Analysis

Abstract

This meta-analysis aims at evaluating the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through November 1st, 2013 without language restrictions. Meta-analysis was conducted with the use of the STATA 12.0 software. The relationships were evaluated by calculating the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Eight case-control studies with a total of 2120 bladder cancer patients and 2061 healthy subjects met the inclusion criteria. Ten common polymorphisms in the CYP1A1 gene were assessed. The results of our meta-analysis suggested that CYP1A1 genetic polymorphisms might be strongly correlated with an increased risk of bladder cancer (allele model: OR=1.23, 95%CI=1.08–1.39, p=0.001; dominant model: OR=1.25, 95%CI=1.07–1.46, p=0.005; respectively), especially for 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. A subgroup analysis was done to investigate the effect of ethnicity on an individual's risk of bladder cancer. Our results revealed positive significant correlations between CYP1A1 genetic polymorphisms and an increased risk of bladder cancer among Asians (allele model: OR=1.33, 95%CI=1.08–1.65, p=0.009; dominant model: OR=1.37, 95%CI=1.02–1.85, p=0.034; respectively), but not among Caucasians (all p<0.05). Our findings provide convincing evidence that CYP1A1 genetic polymorphisms may contribute to susceptibility to bladder cancer, especially for 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms among Asians.

Introduction

Bladder cancer, the most common malignant neoplasm in the urinary system, is the ninth most frequent cancer and is responsible for approximately 330,000 new cases and 130,000 deaths per year worldwide (Ploeg et al., 2009; Jemal et al., 2011). Epidemiological research has suggested that bladder cancer is a multifactorial disease with a wide variety of disease-producing factors such as environmental, genetic, and some new emerging risk factors (Wu et al., 2006; Kiemeney et al., 2009; Kiltie, 2010). During the last decades, cigarette smoking and occupational exposure of aromatic amines have been reported to be implicated in the incidence of bladder cancer (Hung et al., 2004; Jiang et al., 2012). Although the exact cellular and molecular mechanisms leading to the development of bladder cancer remain unclear, it is believed that environmental and genetic factors may contribute to increased susceptibility to bladder cancer (Chu et al., 2013).

Cytochrome-P450 1A1 (CYP1A1) belongs to the large and important superfamily of cytochrome P450 (CYPs) that is involved in the metabolism of many xenobiotic compounds and endogenous lipophilic substances, which can activate procarcinogens into DNA reactive metabolites (Sridhar et al., 2010; van Waterschoot and Schinkel, 2011). Human CYP1A1 gene is located on chromosome 15q22–24 and composed of seven exons (Durocher et al., 1998). It has been commonly known that CYP1A1 is responsible for the activation of procarcinogens to reactive metabolites and is implicated in mediating oxidation, including polycyclic aromatic hydrocarbons and aromatic amines to mutagenic and carcinogenic metabolites (Beedanagari et al., 2009; Jarukamjorn et al., 2010). However, CYP1A1 genetic polymorphisms may lead to alteration or a complete loss in activity of the corresponding metabolizing enzymes, and result in impaired cellular detoxification, which may cause absence of mechanisms for cancer prevention, thereby contributing to susceptibility to bladder carcinogenesis (Ozturk et al., 2011; Cash et al., 2012).

Many previous studies have demonstrated that CYP1A1 genetic polymorphisms may be implicated in the pathogenesis of bladder cancer (Yang et al., 2007; Grando et al., 2009). Nevertheless, contradictory results were also reported in many of the other studies (Brockmoller et al., 1996; Ozturk et al., 2011; Fu and Chen, 2013). Consequently, we performed the present meta-analysis to evaluate the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk.

Materials and Methods

Search strategy

The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without language restrictions. The following keywords and MeSH terms were used: (“SNP” or “mutation” or “genetic polymorphism” or “variation” or “polymorphism” or “single nucleotide polymorphism” or “variant”) and (“urinary bladder neoplasm” or “urinary bladder cancer” or “bladder neoplasm” or “bladder cancer” or “bladder carcinogenesis”) and (“cytochrome P450 1A1” or “CYP1A1” or “cytochrome P-450 CYP1A1”). We also performed a manual search to find other potential articles.

Selection criteria

The included studies should meet all four of the following criteria: (1) the study design should be a clinical cohort or a case-control study that focused on the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk; (2) all patients diagnosed with bladder cancer should be confirmed through histopathologic examinations; (3) the study should provide sufficient information about genotype frequencies of CYP1A1 genetic polymorphisms; and (4) the genotype frequencies should follow the Hardy–Weinberg equilibrium (HWE). If the study could not meet the inclusion criteria, it would be excluded. The most recent or the largest sample size publication was included when the authors published several studies using the same subjects.

Data extraction

Relevant data were systematically extracted from all included studies by two observers by using a standardized form. The researchers collected the following data: language of publication, publication year of article, the first author's surname, geographical location, design of study, sample size, the source of the subjects, genotype frequencies, source of samples, genotyping method, evidence of HWE, and so on.

Quality assessment

Methodological quality was independently assessed by two researchers according to the Newcastle-Ottawa Scale (NOS) criteria (Stang, 2010). The NOS criteria included three aspects: (1) subject selection: 0–4; (2) comparability of subject: 0–2; (3) clinical outcome: 0–3. NOS scores ranged from 0 to 9 with and a score≥7 indicating a good quality.

Statistical analysis

The STATA version 12.0 (Stata Corp, College Station, TX) software was used for meta-analysis. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95%CIs) to evaluate the relationships between common polymorphisms in the CYP1A1 gene and bladder cancer risk. Genotype frequencies of healthy controls were tested for the HWE using the χ² test. The statistical significance of pooled ORs was assessed by the Z test. The Cochran's Q-statistic and I² test were used to evaluate potential heterogeneity between studies (Zintzaras and Ioannidis, 2005). If Q test shows a p<0.05 or I² test exhibits >50%, which indicates significant heterogeneity, the random-effects model was conducted, or else, the fixed-effects model was used. We also performed subgroup and meta-regression analyses to investigate potential sources of heterogeneity. We conducted a sensitivity analysis to assess the influence of single studies on the overall ORs. Begger's funnel plots and Egger's linear regression test were used to investigate publication bias (Peters et al., 2006).

Results

Characteristics of included studies

Initially, the searched keywords identified 53 articles. We reviewed the titles and abstracts of all articles and excluded 24 articles; full texts and data integrity were also reviewed, and 21 articles were further excluded. Finally, eight case-control studies with a total of 2120 bladder cancer patients and 2061 healthy subjects met our inclusion criteria for qualitative data analysis (Brockmoller et al., 1996; Yang et al., 2007; Srivastava et al., 2008; Grando et al., 2009; Villanueva et al., 2009; Ozturk et al., 2011; Berber et al., 2013; Fu and Chen, 2013). Publication years of the eligible studies ranged from 1996 to 2013. Figure 1 shows the selection process of eligible articles. Distribution of the number of topic-related literatures in the electronic database during the last decade is shown in Figure 2. Overall, five studies were conducted among Asians and three studies were conducted among Caucasians. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in four studies, two studies used allele specific-PCR (AS-PCR) method, while only one study used the TaqMan assay method, and one study used PCR-confronting two-pair primers (PCR-CTPP). Ten common polymorphisms (4889A>G, 462A>G, 728C>T, 11599G>C, 17961C>T, 2455A>G, 3810T>C, 113T>C, 139A>G, and 6235C>T) in CYP1A1 gene were assessed. Genotype frequencies of controls were all in HWE (all p>0.05). None of the studies deviated from the HWE (all p>0.05). NOS scores of all included studies were ≥5. We summarized the study characteristics and methodological quality in Table 1.

FIG. 1.

Flowchart of literature search and study selection. Eight case-control studies were included in this meta-analysis.

FIG. 2.

Distribution of the number of topic-related literature in the electronic database during the last decade.

Table 1.

Baseline Characteristics and Methodological Quality of All Included Studies

				Sample size		Gender (M/F)		Age (years)
First author	Year	Country	Ethnicity	Case	Control	Case	Control	Case	Control	Genotyping method	SNP	HWE test (p-value)	NOS score
Fu	2013	China	Asian	99	100	88/11	89/11	60.6±12.5	57.4±11.8	PCR-CTPP	4889A/G	0.336	7
Berber	2013	Iran	Asian	114	114	103/11	103/11	65.1±9.3	63.2±5.8	AS-PCR	462A/G	0.886	8
Ozturk	2011	Turkey	Asian	176	97	158/18	—	61.5±13.3	56.6±12.8	PCR-RFLP	462A/G	0.504	6
Villanueva	2009	Spain	Caucasian	1107	1032	—	—	—	—	TaqMan	728C/T	0.786	6
											11599G/C	0.176
											17961C/T	0.563
Grando	2009	Brazil	Caucasian	100	100	73/27	73/27	65.8±10.4	66.6±10.6	AS-PCR	2455A/G	0.189	7
Srivastava	2008	India	Asian	106	160	—	—	55.5±13.8	51.8±0.6	PCR-RFLP	3810T/C	0.408	5
											113T/C	0.382
											139A/G	0.769
Yang	2007	China	Asian	44	85	30/14	47–80	—	—	PCR-RFLP	3810T/C	0.349	5
Brockmoller	1996	Germany	Caucasian	374	373	251/123	242/131	71	65.8	PCR-RFLP	6235C/T	0.730	7
											4889A/G	0.336

M, male; F, female; SNP, single nucleotide polymorphism; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; PCR-CTPP, polymerase chain reaction-restriction-confronting two-pair primers; AS-PCR, allele specific-polymerase chain reaction-restriction; HWE, Hardy–Weinberg equilibrium; NOS, the Newcastle-Ottawa Scale.

Quantitative data synthesis

Meta-analysis findings on the relationships of CYP1A1 genetic polymorphisms with the risk of bladder cancer were shown in Table 2. The random-effects model was conducted due to obvious heterogeneity existing between studies. The results of our meta-analysis suggested that CYP1A1 genetic polymorphisms might be strongly correlated with an increased risk of bladder cancer (allele model: OR=1.23, 95%CI=1.08–1.39, p=0.001; dominant model: OR=1.25, 95%CI=1.07–1.46, p=0.005; respectively), especially for 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms (Fig. 3).

FIG. 3.

Forest plots for the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk under the allele and dominant models.

Table 2.

Meta-Analysis of the Relationships of CYP 1 A 1 Genetic Polymorphisms with the Risk of Bladder Cancer

	M allele vs. W (Allele model)			WM+MM vs. WW (Dominant model)			MM vs. WW+WM (Recessive model)			MM vs. WW (Homozygous model)			MM vs. WM (Heterozygous model)
	OR	95%CI	p	OR	95%CI	p	OR	95%CI	p	OR	95%CI	p	OR	95%CI	p
Overall	1.23	1.08–1.39	0.001	1.25	1.07–1.46	0.005	1.28	1.05–1.57	0.016	1.49	1.15–1.93	0.003	1.16	0.94–1.43	0.169
SNP type
4889A>G	1.14	0.71–1.82	0.594	1.11	0.63–1.94	0.728	1.72	0.40–7.40	0.466	1.75	0.40–7.68	0.456	1.67	0.37–7.49	0.505
462A>G	1.11	0.77–1.61	0.567	1.08	0.71–1.63	0.721	1.79	0.47–6.87	0.397	1.79	0.46–6.91	0.398	1.75	0.44–6.97	0.426
728C>T	1.19	0.97–1.45	0.090	1.17	0.94–1.46	0.158	1.71	0.82–3.58	0.151	1.76	0.84–3.67	0.133	1.55	0.73–3.31	0.256
11599G>C	1.24	1.05–1.46	0.009	1.30	1.08–1.57	0.007	1.21	0.77–1.92	0.411	1.31	0.83–2.09	0.248	1.01	0.63–1.64	0.957
17961C>T	1.01	0.88–1.15	0.927	0.99	0.83–1.19	0.937	1.05	0.78–1.41	0.744	1.04	0.76–1.42	0.801	1.06	0.78–1.44	0.712
2455A>G	1.81	1.05–3.10	0.033	1.99	1.07–3.73	0.030	1.70	0.40–7.32	0.475	2.03	0.47–8.83	0.344	1.02	0.22–4.77	0.978
3810T>C	1.43	1.04–1.96	0.027	1.54	1.02–2.33	0.039	1.71	0.81–3.64	0.162	2.04	0.93–4.44	0.074	1.40	0.64–3.09	0.401
113T>C	2.08	1.45–2.97	0.000	2.93	1.71–5.02	0.000	2.19	1.11–4.29	0.023	3.83	1.79–8.20	0.001	1.43	0.70–2.93	0.321
139A>G	1.03	0.67–1.58	0.902	1.04	0.62–1.72	0.887	1.01	0.28–3.66	0.992	1.02	0.28–3.75	0.976	0.98	0.26–3.73	0.978
6235C>T	1.03	0.71–1.49	0.889	1.01	0.68–1.50	0.956	1.47	0.24–8.83	0.676	1.47	0.24–8.84	0.676	1.47	0.24–9.16	0.677
Ethnicity
Asians	1.33	1.08–1.65	0.009	1.37	1.02–1.85	0.034	1.79	1.17–2.73	0.007	2.27	1.45–3.56	0.000	1.41	0.91–2.20	0.126
Caucasians	1.15	1.00–1.32	0.054	1.16	0.99–1.37	0.064	1.16	0.92–1.46	0.200	1.20	0.94–1.52	0.140	1.09	0.86–1.39	0.463
Genotyping method
Non-PCR-PFLP	1.16	1.02–1.31	0.019	1.18	1.02–1.36	0.028	1.17	0.94–1.48	0.166	1.21	0.96–1.53	0.113	1.11	0.87–1.40	0.410
PCR-RFLP	1.30	1.01–1.67	0.040	1.36	0.97–1.91	0.075	1.77	1.14–2.73	0.010	2.27	1.43–3.62	0.001	1.38	0.88–2.18	0.163

W, wild allele; M, mutant allele; WW, wild homozygote; WM, heterozygote; MM, mutant homozygote; OR, odds ratio; 95%CI, 95% confidence interval.

A subgroup analysis was done to investigate the effect of ethnicity on an individual's risk of bladder cancer (Fig. 4). Our results revealed positive significant correlations between CYP1A1 genetic polymorphisms and an increased risk of bladder cancer among Asians (allele model: OR=1.33, 95%CI=1.08–1.65, p=0.009; dominant model: OR=1.37, 95%CI=1.02–1.85, p=0.034; respectively), but not among Caucasians (all p<0.05). We also performed a subgroup analysis by genotyping method; the results indicated significant associations between CYP1A1 genetic polymorphisms and an increased risk of bladder cancer in both PCR-RFLP and non-PCR-RFLP subgroups (as shown in Table 2).

FIG. 4.

Subgroup analyses by ethnicity and genotyping method of the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk under the allele and dominant models.

Meta-regression analyses results confirmed that ethnicity might be a main source of heterogeneity (as shown in Table 3). The results of sensitivity analysis indicated that the overall pooled ORs could not be affected by single study (Fig. 5). No evidence for asymmetry was observed in the Begger's funnel plots (Fig. 6). Egger's test also failed to reveal any evidence of publication bias (allele model: t=1.41, p=0.189; dominant model: t=1.33, p=0.212).

FIG. 5.

Sensitivity analysis of the summary odds ratio coefficients on the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk under the allele and dominant models.

FIG. 6.

Begger's funnel plot of publication biases on the relationships between CYP1A1 genetic polymorphisms and bladder cancer risk under the allele and dominant models.

Table 3.

Univariate and Multivariate Meta-Regression Analyses of Potential Source of Heterogeneity

					95%CI
Heterogeneity factors	Coefficient	SE	Z	p	LL	UL
Publication year
Univariate	0.007	0.018	0.39	0.699	−0.028	0.042
Multivariate	0.033	0.045	0.73	0.466	−0.055	0.120
SNP type
Univariate	0.017	0.026	0.66	0.510	−0.034	0.068
Multivariate	0.052	0.051	1.01	0.310	−0.048	0.152
Ethnicity
Univariate	−0.153	0.122	−1.26	0.208	−0.392	0.086
Multivariate	−0.025	0.374	−0.07	0.946	−0.758	0.707
Genotyping method
Univariate	−0.108	0.130	−0.83	0.407	−0.363	0.147
Multivariate	−0.005	0.423	−0.01	0.990	−0.835	0.824

SE, standard error; UL, upper limit; LL, lower limit.

Discussion

CYP1A1, a member of CYP1 family, is a hepatic enzyme that is widely distributed in extra-hepatic tissues such as the lungs, kidneys, gastrointestinal tract, throat, placenta, and lymphocytes (Delescluse et al., 2000; Stejskalova and Pavek, 2011). It should be noted that CYP1A1 serves as a phase I detoxification enzyme which is implicated in the activation of pro-carcinogens and protoxin, and the subsequent generation of strong electrophilic compounds is capable of interacting with intracellular macromolecules such as DNA, RNA, proteins, and other nucleophilic group (Suchocki et al., 2010; Masek et al., 2011). Consequently, the metabolic activation may destroy the cell structure and produce inactivated or abnormal enzymes, and inevitably induce CYP1A1 mutations or inhibit its expression, thereby affecting the metabolic and transport pathways of estrogens and evoking programmed cell death or tumorigenesis (Young et al., 2010; Chen et al., 2012). Therefore, it has been postulated that polymorphic variants conferring elevated CYP1A1 enzyme activity may lead to increased production of catechol estrogens and be conducive to the development of bladder cancer (Fontana et al., 2009; Yousef et al., 2012).

In the present meta-analysis, our findings revealed that bladder cancer patients had a higher frequency of CYP1A1 genetic polymorphisms than healthy controls, suggesting that common polymorphisms in the CYP1A1 gene may be causative factors for the incidence of bladder cancer. Although the exact function of CYP1A1 in the pathogenesis of bladder cancer is not yet poorly understood, a potential explanation might be that CYP1A1 genetic polymorphisms may increase the level of its expression through the aryl hydrocarbon receptor (AhR), which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes and involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis (Nukaya et al., 2010; Mohebati et al., 2012). Furthermore, dysregulation of these pathways caused by CYP1A1 genetic polymorphisms may be closely linked to the development and progression of bladder cancer (Androutsopoulos et al., 2009). A previous study also demonstrated that the A/G and G/G variants of the CYP1A1 gene may contribute to the development of bladder cancer (Grando et al., 2009). Since heterogeneity obviously existed, we performed stratified analyses based on ethnicity and genotyping method. Our findings suggested that CYP1A1 genetic polymorphisms were associated with an increased risk of bladder cancer among Asians, but not among Caucasians, revealing that ethnic differences may cause heterogeneity between studies concerning the role of CYP1A1 genetic polymorphisms in the pathogenesis of bladder cancer. This may be explained that natural selection and random genetic drift may affect an individual's susceptibility to bladder cancer. Meta-regression analysis also confirmed that ethnicity might be a main source of heterogeneity. In short, the results of our meta-analysis were consistent with previous studies that CYP1A1 genetic polymorphisms may contribute to susceptibility to bladder cancer.

The current meta-analysis also had many limitations that should be acknowledged. First, due to relatively small sample size, our results lacked sufficient statistical power to assess the effects of CYP1A1 genetic polymorphisms on susceptibility to bladder cancer. Second, meta-analysis is a retrospective study that may lead to subject selection bias, thereby affecting the reliability of our results. Third, our meta-analysis failed to obtain original data from the included studies, which may limit a further evaluation of potential roles of CYP1A1 genetic polymorphisms in bladder carcinogenesis. Although our study has many limitations, this is the first meta-analysis that focused on the relationships of CYP1A1 genetic polymorphisms with the risk of bladder cancer. Furthermore, we performed a highly sensitive literature search strategy for electronic databases. A manual search of the reference lists from the relevant articles was also conducted to find other potential articles. The selection process of eligible articles was based on strict inclusion and exclusion criteria. Importantly, a rigorous statistical analysis of SNP data provided a basis for pooling of information from individual studies.

In conclusion, our findings provide convincing evidence that CYP1A1 genetic polymorphisms may contribute to susceptibility to bladder cancer, especially for 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms among Asians. Thus, CYP1A1 genetic polymorphisms may be utilized as potential biomarkers for an early diagnosis of bladder cancer. However, due to the limitations mentioned earlier, more research with a larger sample size is needed to provide a more representative statistical analysis.

Footnotes

Acknowledgments

This study was supported by the Science and Technology Research Project of the Higher Education Department of Liaoning Province (No. L2010695). The authors would like to acknowledge the helpful comments on this article received from their reviewers.

Disclosure Statement

The authors declare that they have no conflicts of interest.

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