Abstract
Several studies reported Prostate stem cell antigen (PSCA) rs2294008 was susceptibly associated with bladder cancer (BC) risk. However, the results were not entirely consistent. The aim of this study was to investigate the association between rs2294008 and BC risk. Comprehensive meta-analysis was preformed to provide a more precise assessment of the association between rs2294008 and BC risk. Twenty five studies involving 14,244 BC patients and 53,963 controls were included in our meta-analysis. The crude odds ratios (ORs) and the 95% confidence intervals (95% CIs) were used to evaluate the strength of the association. Pooled results indicated that the PSCA variant rs2294008-T was significantly connected with an increased risk of BC (OR = 1.15, 95% CI = 1.12-1.18, P(z) < 0.0001). Moreover, stratified analyses showed that rs2294008 significantly increased BC risk in European (OR = 1.10, 95% CI = 1.05-1.15, P(z) < 0.0001), North American (OR = 1.18, 95% CI = 1.12-1.24, P(z) < 0.0001), and Asian (OR = 1.17, 95% CI = 1.13-1.22, P(z) < 0.0001). In conclusion, our meta-analysis demonstrated that the PSCA rs2294008 is a risk factor for BC in European, Asian and North American. Further large case-control studies are needed to assess the relationship in other populations. Biologically functional studies are needed to verify the molecular mechanisms in the pathogenesis of BC.
Keywords: Prostate stem cell antigen, rs2294008, bladder cancer, meta-analysis
Introduction
Bladder cancer (BC) is the most common malignancy of urinary system with 74,690 new cases and 15,580 deaths expected in the United States in 2014 [1]. BC is occurred in the bladder mucosa, which is a kind of malignant tumor. Tobacco [2] and occupational exposure [3] are regarded as the main environmental risk factors for BC. Genetic factors are also contributed to its origin, some through interaction with environmental factors [4]. Recent genome-wide expression and sequencing studies identify that genes and pathways play key roles in the pathogenesis of urothelial cancers [5].
Prostate stem cell antigen (PSCA) gene encoded a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. It was up-regulated in BC and was thought to abet cancer progression [6]. PSCA in voided urine specimens had been certified to be an adjunct marker for cytological diagnosis of urothelial transitional cell carcinoma [7]. Elsamman E et al [8] had proved that the PSCA expression was an independent predictor of recurrence in superficial BC. Different PSCA expression might play an important role in counteracting the natural immune response by activating the genes downstream of the IFNalpha/beta receptor [6]. Genome wide association studies (GWAS) demonstrated that genetic variation of PSCA might associate with the development of BC in Japanese population [9]. Results of Zhang W et al [10] suggested that PSCA gene variation had a potential effect on its expression and cancer risk. Study of Fu et al [11] suggested that two PSCA SNPs (rs2294008 and rs2978974) may be important for BC susceptibility, possibly through different mechanisms including influencing the mRNA expression and interacting with regulatory factors.
The polymorphism PSCA rs2294008-T might play allele-specific roles in cancer development [12]. This variant was showed to be significant association with BC risk in Japanese [9], and North American population [13]. It was also considered to be a significant predictor of genetic susceptibility to bladder cancer in Chinese [14]. To date, several studies had reported PSCA rs2294008 was susceptibly associated with BC risk. However, the results were not entirely consistent. Especially the results of different ethnicity are controversial [11,13]. Thus, we performed a meta-analysis to clarify the relationship between the PSCA rs2294008 (C/T) and BC risk in multiple populations.
Materials and methods
Publication search strategy
The meta-analysis was performed to examine the association between PSCA polymorphism and BC risk. We systematically identified publications in multiple literature databases including PubMed, Google, and China National Knowledge Infrastructure (CNKI). The following keywords included different combinations of the terms: “PSCA”, “polymorphism”, “variation”, “rs2294008”, paired with “bladder cancer”, respectively. Full texts were read to find the interested information. References listed on the retrieved articles and previous reviews on this subject were searched to appraise other studies of potential relevance. Meanwhile, the papers should be published in Chinese or English update to 2015.
Inclusion and exclusion criteria
The selected studies must base on the criteria as follows: (1) the study must evaluate the relationship between PSCA rs2294008 and BC risk; (2) the study was a case-control or a prospective design; (3) the study contained the complete data with genotype and allele frequencies; (4) the study must provide sufficient data to calculate odds ratio (OR) and 95% confidence interval (95% CI); (5) the genotype distribution of controls was in Hardy-Weinberg equilibrium (HWE).
The studies were excluded if genotype distribution in the controls demonstrated departure from HWE (P < 0.05). In addition, case-only studies, reviews articles, conference abstract, and studies without detailed data were excluded.
Data extraction
All data were independently extracted by two authors based on a standard protocol. Disagreements were settled down by group discussion until a consensus was reached. When multiple publications from a particular research group reported data from overlapping samples, the study reporting the largest or latest dataset was included. Information was collected from enrolled study, including first author, publication year, total number of cases and controls, genetic distribution, OR and 95% CI.
Statistical analysis
The strength of association between PSCA rs2294008 and BC susceptibility was estimated by calculating OR with the corresponding 95% CI. Statistical heterogeneity between studies was estimated using the Chi-Square test and inconsistency index (I2 statistic). A value I2 > 50% indicated a significant heterogeneity among the studies. Random-effects model (the Der Simonian and Laird method) was used to calculate the combined OR with high heterogeneity (I2 > 50%); otherwise a fixed-effects model (the Mantel-Haenszel method) would be applied. Publication bias was estimated by the Begg funnel plots and Egger regression test. The meta-analysis was performed by the Stata software (version 11.0, Stata Corporation, College Station, TX). Z test was used to conclude the pooled OR and a P < 0.05 was considered to be statistically significant.
Results
Characteristics of included studies
As shown in Figure 1, we preliminarily identified 50 articles concerning the association for PSCA rs2294008 and disease in the database of PubMed, Google, and CNKI up to May 5, 2015. Finally, 25 studies from 7 articles were eligible for this meta-analysis. The Characteristics of retrieved studies were listed in Table 1. The detailed information included the first author, publication year, ethnicity, country, the number of cases and controls, genotyping and control selection. Among the screened publications, 12 studies were from European, 8 studies were from North American, and 5 studies were from Asian. According to the selection of control in the 25 studies, there were 10 studies were hospital-based controls and 15 studies were population-based controls.
Figure 1.
Flow diagram depicts literature search and study selection.
Table 1.
Characteristics of studies included in the meta-analysis
| First author | Ethnicity | Country | Case/control | Genotyping | Control selection |
|---|---|---|---|---|---|
| Wu et al 2009 | North American | Texas | 969/957 | Illumina | HB |
| Wu et al 2009 | North American | New Hampshire | 800/912 | Taqman | PB |
| Wu et al 2009 | North American | MSKCC | 149/152 | Taqman | HB |
| Wu et al 2009 | European | Iceland | 551/28757 | Illumina | PB |
| Wu et al 2009 | European | Netherlands | 1276/1831 | Illumina | PB |
| Wu et al 2009 | European | UK | 706/514 | Taqman | HB |
| Wu et al 2009 | European | Italy-Torino | 357/310 | Taqman | HB |
| Wu et al 2009 | European | Italy-Brescia | 182/190 | Taqman | HB |
| Wu et al 2009 | European | Sweden | 335/909 | Taqman | PB |
| Wu et al 2009 | European | Belgium | 192/380 | Taqman | PB |
| Wu et al 2009 | European | Spain | 172/1362 | Taqman | HB |
| Wu et al 2009 | European | Eastern Europe | 214/509 | Taqman | HB |
| Wang et al 2010 | Asian | China | 581/580 | PCR-RFLP | HB |
| Fu et al 2012 | North American | ATBC | 401/707 | Illumina | PB |
| Fu et al 2012 | North American | CPS-II | 687/730 | Illumina | PB |
| Fu et al 2012 | European | NEBCS-ME/VT | 630/759 | Illumina | PB |
| Fu et al 2012 | North American | PLCO | 708/1874 | Illumina | PB |
| Fu et al 2012 | European | SPBC | 1106/1050 | Illumina | PB |
| Fu et al 2012 | North American | TXBC1 | 968/957 | Illumina | PB |
| Fu et al 2012 | North American | TXBC2 | 602/949 | TaqMan | PB |
| Fu et al 2012 | European | NEBCS-NH | 314/323 | TaqMan | PB |
| Ma et al 2013 | Asian | China | 184/962 | MALDI-TOF | PB |
| Wang et al 2013 | Asian | China | 1210/1008 | TaqMan | PB |
| Matsuda et al 2014 | Asian | Japan | 539/5581 | Illumina | HB |
| Lee et al 2014 | Asian | Korea | 411/1700 | HRM | HB |
a: PB: Population based; HB: Hospital based; MSKCC: Memorial Sloan Kettering Cancer Center; ATBC: Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CPS-II: The American Cancer Society Cancer Prevention Study II Nutrition Cohort; NEBCS-ME/VT: The New England Bladder Cancer Study from Maine and Vermont; PLCO: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; SPBC: The Spanish Bladder Cancer Study; TXBC1: Texas Bladder Cancer Study discovery set; TXBC2: Texas Bladder Cancer Study validation set; NEBCS-NH: New England Bladder Cancer Study from New Hampshire.
The distribution of rs2294008 genotypes between cancer and control groups in the meta-analysis were listed in the Table 2. Genotype distributions of the control subgroups in the studies were consistent with HWE (P > 0.05).
Table 2.
Distribution of rs2294008 genotypes between cancer and control groups included in the meta-analysis
| First author | Case (CC/CT/TT) | Case (C/T) | Control (CC/CT/TT) | Control (C/T) |
|---|---|---|---|---|
| Wu XF et al 2009 | na | 967/971 | na | 1060/854 |
| Wu XF et al 2009 | na | 802/798 | na | 1007/817 |
| Wu XF et al 2009 | na | 141/157 | na | 169/135 |
| Wu XF et al 2009 | na | 568/534 | na | 30540/26974 |
| Wu XF et al 2009 | na | 1350/1202 | na | 2018/1644 |
| Wu XF et al 2009 | na | 765/647 | na | 590/438 |
| Wu XF et al 2009 | na | 387/327 | na | 348/272 |
| Wu XF et al 2009 | na | 201/163 | na | 212/168 |
| Wu XF et al 2009 | na | 326/344 | na | 1000/818 |
| Wu XF et al 2009 | na | 192/192 | na | 402/358 |
| Wu XF et al 2009 | na | 193/151 | na | 1539/1185 |
| Wu XF et al 2009 | na | 205/23 | na | 566/452 |
| Wang SZ et al 2010 | 272/259/50 | 803/359 | 316/220/44 | 852/308 |
| Fu YP et al 2012 | 71/227/103 | 369/433 | 163/370/171 | 696/712 |
| Fu YP et al 2012 | 162/365/158 | 689/681 | 209/363/154 | 781/671 |
| Fu YP et al 2012 | 165/325/139 | 655/603 | 223/369/167 | 815/703 |
| Fu YP et al 2012 | 170/364/157 | 704/678 | 543/910/406 | 1996/1722 |
| Fu YP et al 2012 | 315/572/216 | 1202/1004 | 308/529/210 | 1145/949 |
| Fu YP et al 2012 | 234/500/234 | 968/968 | 302/456/199 | 1060/854 |
| Fu YP et al 2012 | 166/297/139 | 629/575 | 267/479/203 | 1013/885 |
| Fu YP et al 2012 | 80/154/80 | 314/314 | 92/169/62 | 353/293 |
| Ma ZC et al 2013 | 84/80/11 | 248/102 | 543/355/64 | 1441/483 |
| Wang P et al 2013 | 604/509/97 | 1717/703 | 566/376/66 | 1508/508 |
| Matsuda K et al 2014 | 61/228/241 | 350/710 | 730/2416/2079 | 3876/6574 |
| Lee JH et al 2014 | 79/222/119 | 380/460 | 414/818/468 | 1646/1754 |
Results of meta-analysis
The main results of the meta-analysis were presented in the Table 3. A total of 14,244 BC patients and 53,963 controls were pooled in this meta-analysis. Significantly increased BC risk was found for the rs2294008-T carriers (OR = 1.15, 95% CI = 1.12-1.18, P(z) < 0.0001, I2 = 0.0%, Figure 2). Considering the ethnicity is a potential impact of the confounding factors. We performed a subgroup analysis by ethnicity. The results showed similar significant associations of rs2294008 with BC risk in European (OR = 1.10, 95% CI = 1.05-1.15, P(z) < 0.0001, I2 = 0.0%, Table 3), North American (OR = 1.18, 95% CI = 1.12-1.24, P(z) < 0.0001, I2 = 0.0%, Table 3), and Asian (OR = 1.17, 95% CI = 1.13-1.22, P(z) < 0.0001, I2 = 0.0%, Table 3). Subgroup analysis by selection of controls showed significant association in both hospital based control group (OR = 1.18, 95% CI = 1.12-1.25, P(z) < 0.0001, I2 = 0.0%, Table 3) and the population based control group (OR = 1.14, 95% CI = 1.11-1.18, P(z) < 0.0001, I2 = 1.6%, Table 3). Publication bias was evaluated by Begg’s funnel plot and Egger’s test. There was no evidence of publication bias for the association between rs2294008 and BC risk (P(egger) = 0.816, P(Begg) = 0.591, Figure 3).
Table 3.
Heterogeneity test of rs2294008 association studies by subgroup analyses
| Group | Studies/stages, n | OR (95% CI) | Weight% | Z | P (z) | I2 | P | τ2 | Heterogeneity statistic |
|---|---|---|---|---|---|---|---|---|---|
| Ethnicity | |||||||||
| European | 12 | 1.10 (1.05-1.15) | 31.17 | 4.01 | < 0.0001 | 0.00% | 0.497 | 0 | 10.38 |
| North American | 8 | 1.18 (1.12-1.24) | 26.02 | 6.23 | < 0.0001 | 0.00% | 0.528 | 0 | 6.1 |
| Asian | 5 | 1.17 (1.13-1.22) | 42.82 | 7.77 | < 0.0001 | 0.00% | 0.877 | 0 | 1.2 |
| Control selection | |||||||||
| Hospital Base | 10 | 1.18 (1.12-1.25) | 21.44 | 5.79 | < 0.0001 | 0.00% | 0.601 | 0 | 7.34 |
| Population Base | 15 | 1.14 (1.11-1.18) | 78.55 | 8.59 | < 0.0001 | 1.60% | 0.433 | 0.0001 | 14.22 |
| Overall | 25 | 1.15 (1.12-1.18) | 100.00 | 10.5 | < 0.0001 | 0.00% | 0.540 | 0 | 22.67 |
Figure 2.
Meta-analysis of 25 association studies between rs2294008 and BC.
Figure 3.
Funnel plot for the studies of the association of BC and rs2294008.
Discussion
In this work, we analyzed 25 studies among more than 68,200 participants to verify the association between PSCA rs2294008 and BC risk. Our results showed that PSCA rs2294008 was associated with BC risk in multiple populations, including European, North American and Asian.
PSCA was reported to be a cell-surface antigen in the diagnosis and treatment of bladder or pancreatic cancers [15,16]. The level of PSCA expression may be involved in cell proliferation, and associated to the tumor growth and metastasis formation [17,18]. SNP rs2294008 was located on the chromosome 8q24.3, in the PSCA gene. The T allele of rs2294008 was a missense variant located in the putative translation initiation codon, which could lead to 9 amino acid deletion in the signal peptide and reduce the transcriptional activity of an upstream fragment of PSCA gene [19]. This polymorphism had been studied in different disease such as duodenal ulcer [20], gastric cancer [21] and breast cancer [22].
Previous meta-analyses had investigated the role of the PSCA rs2294008 in BC risk [23-25]. Five to nine studies were subsequently performed to certify the positive association in Asians and Caucasians. However, some results were incongruous. This might be due to a lack of power for some studies or genetic heterogeneity in PSCA gene. Our meta-analysis of rs2294008 included 25 publication studies and was involved with 14,244 BC patients and 53,963 controls in European, North American and Asian populations. Our results establish that PSCA rs2294008 was able to predict a 15% increased risk of BC.
Meta-analysis was an important method to improve the precision and accuracy, to analyze and quantify the published results. There were some advantages in our study. Such as the genotype distributions in the control groups were conformed to the HWE (P > 0.05) in all the enrolled studies. All the detailed information was collected, such as age, gender matched or other factors associated with cancer risk. No visual publication bias was found in the different analyses. Nevertheless, several limitations should be noted. First, three ethnic groups (European, North American and Asian) were included in our meta-analysis. However, there was no study based on patients with an African background. Larger sample size studies based on Africans were warranted to validate the association between the rs2294008 polymorphism and BC risk in the further study. Second, only publications written in Chinese and English included in this meta-analysis. Some relevant published reports in other languages might be eligible for this meta-analysis were missed. Additionally, gene-gene and gene-environment interactions should be considered in further studies.
In conclusion, our meta-analysis demonstrated that the PSCA rs2294008 is a risk factor for BC in European, Asian and North American. Further large case-control studies are needed to assess the relationship in other populations. Biologically functional studies are needed to verify the molecular mechanisms in the pathogenesis of BC.
Acknowledgements
This study was supported by the grants from the Ningbo People of Science and Technology Projects (2015C50005), Ningbo Yinzhou Social Development Research Projects, Ningbo Natural Science Foundation (2014A610260, 2015A610232), Zhejiang Traditional Chinese Medicine Science and Technology Projects (2015ZB100).
Disclosure of conflict of interest
None.
References
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