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. 2012 Apr 6;138(8):1339–1345. doi: 10.1007/s00432-012-1210-6

The PSCA polymorphisms derived from genome-wide association study are associated with risk of gastric cancer: a meta-analysis

Danni Shi 1, Shizhi Wang 1, Dongying Gu 3, Dongmei Wu 2, Meilin Wang 2, Haiyan Chu 1, Na Tong 2, Lan Ma 1, Dongyan Zhong 1, Zhengdong Zhang 1,2,✉
PMCID: PMC11824355  PMID: 22481254

Abstract

Purpose

Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored 123-aa protein related to the cell-proliferation inhibition and/or cell-death induction activity. Many studies had reported the role of PSCA rs2294008 C > T and rs2976392 G > A polymorphisms on gastric cancer risk.

Methods

To investigate a more precise estimation of the relationships, we performed a meta-analysis on 9 case–control studies included 10,746 cases and 9,158 controls. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the association.

Results

For PSCA rs2294008 C > T polymorphism, there was a significantly increased risk of gastric cancer in all genetic models (TT/TC vs. CC: OR = 1.61, 95 % CI = 1.35–1.91; TT vs. TC/CC: OR = 1.33, 95 % CI = 1.24–1.42). Similar results were also observed for PSCA rs2976392 G > A polymorphism (AA/AG vs. GG: OR = 1.69, 95 % CI = 1.24–2.31; AA vs. AG/GG: OR = 1.36, 95 % CI = 1.24–1.50). In the stratified analysis by ethnicity of rs2294008, an increased gastric cancer risk was found in both Asians (TT vs. TC/CC: OR = 1.31, 95 % CI = 1.22–1.42) and Europeans (TT/TC vs. CC: OR = 1.42, 95 % CI = 1.18–1.71). Furthermore, when stratified by clinicopathologic characteristics of tumor location and histology, a higher risk on non-cardia compared with cardia gastric cancer (TT vs. TC/CC: OR = 1.43, 95 % CI = 1.12–1.83) as same as diffused compared with intestinal gastric cancer (TT vs. TC/CC: OR = 1.29, 95 % CI = 1.13–1.49) was observed.

Conclusion

These findings supported that PSCA rs2294008 C > T and rs2976392 G > A polymorphisms may contribute to the susceptibility to gastric cancer, particular in non-cardia or diffused gastric cancer.

Keywords: PSCA, Genetic variation, Susceptibility, Gastric cancer, GWAS, Meta-analysis

Introduction

Gastric cancer is estimated to be the fourth most common cancer and the second leading cause of cancer-related death worldwide, and approximately 700,000 people die of this malignancy annually (Parkin et al. 2005). Multiple environmental and lifestyle factors are found to be associated with risk of gastric cancer, including a diet poor in fresh fruits and vegetables or rich in salt, tobacco smoking, alcohol consumption and Helicobacter pylori (H. pylori) infection (Zhang et al. 1997). Although the H. pylori is the major acquired etiologic agent responsible for gastric carcinogenesis (Correa et al. 1990; Talley et al. 1991) and the prevalence of H. pylori infection ranges from 40 to 80 % in humans, only a small proportion (<3 %) of infected individuals develops the cancer (Peek and Blaser 2002), suggesting that genetic alteration plays important roles in gastric carcinogenesis.

Prostate stem cell antigen (PSCA), a glycosylphosphatidylinositol-anchored 123-aa protein related to the Ly-6 family of cell-surface proteins (Reiter et al. 1998), is not only widely expressed in normal prostate and over-expressed in a majority of prostate cancer, but also found in non-prostatic malignancies including gastric cancer, bladder cancer, pancreatic cancer and clear cell renal cell carcinoma (Argani et al. 2001; Elsamman et al. 2006; Sakamoto et al. 2008; Wang et al. 2010). PSCA maps on chromosome 8q24.2 (Reiter et al. 1998) and consists of 3 exons and 2 introns. The most extensively studied single nucleotide polymorphisms (SNPs) in PSCA are rs2294008 C > T and rs2976392 G > A. In a recent genome-wide association study (GWAS) of gastric cancer in Asian populations, Sakamoto et al. identified two SNPs, rs2294008 and rs2976392, which were associated with the susceptibility of diffuse-type gastric cancer. In addition, a number of studies have investigated the role of these two polymorphisms in gastric cancer (Sakamoto et al. 2008; Matsuo et al. 2009; Wu et al. 2009; Lu et al. 2010; Ou et al. 2010; Lochhead et al. 2011; Sala et al. 2011; Song et al. 2011; Zeng et al. 2011). Nevertheless, majority of results of these studies are similar, the strengths are different. Considering the extensive role of PSCA in the carcinogenic process, we performed a meta-analysis on all eligible case–control studies to estimate the gastric cancer risk as well as to quantify the potential between study heterogeneity. Another SNP reported by Matsuo et al., rs2976391 A > C (Matsuo et al. 2009), was excluded due to relatively fewer published studies, and the sample size of this study is too small to be included for a meta-analysis.

Materials and methods

Identification and eligibility of relevant studies

All the case–control studies were identified by a database of PubMed, using the following key words: “PSCA,” “polymorphism” and “gastric cancer.” The search was limited to human-associated studies without language constraints. In addition, references of retrieved publications were also screened by a manual search. If there was more than one study with the same population by different investigators or overlapping data by the same authors, we selected the most recent or complete articles with the largest number of subjects. Studies included in our meta-analysis had to meet the following criteria: (1) use an independent case–control design, (2) evaluation of the PSCA rs2294008 C > T or rs2976392 G > A polymorphisms and gastric cancer risk and (3) contain available genotype frequency. Those without controls and duplicate of previous publication were excluded.

Data extraction

Two investigators independently extracted the data and reached consensus on all items. In the present study, the following information was sought from each publication: the first author’s last name, year of publication, country of origin, ethnicity, source of controls (population- or hospital-based controls), genotyping method and number of genotyped cases and controls. Different ethnic descents were categorized as European and Asian. For study including the subjects of different countries of origin group, we extracted data separately whenever possible.

Statistical analysis

The genotype frequencies of PSCA rs2294008 C > T and rs2976392 G > A polymorphisms among the controls were assessed for Hardy–Weinberg equilibrium (HWE) by χ2 test. The strength of the associations between PSCA rs2294008 C > T and rs2976392 G > A polymorphisms and gastric cancer risk was measured by odds ratios (ORs) with 95 % confidence intervals (CIs). The statistical significance of the pooled OR was determined with the Z-test. For rs2294008 C > T polymorphism, we firstly estimated the risks of the variant TT or TC genotype on gastric cancer, compared with the wild-type CC homozygote and then evaluated the risks of TT/TC versus CC and TT versus TC/CC on gastric cancer, assuming dominant and recessive effects of the variant T allele, respectively. For rs2976392 G > A polymorphism, we evaluated the same effects. Stratified analyses were also performed by ethnicity, source of controls and clinicopathologic characteristics.

The statistical heterogeneity among studies was assessed with χ2-based Q-test (Higgins and Thompson 2002), and a P value of <0.10 was considered significant. The summary OR estimate of each study was calculated by the random-effects model (the DerSimonian and Laird method) (DerSimonian and Laird 1986); otherwise, fixed-effects model (the Mantel–Haenszel method) was used (Mantel and Haenszel 1959). To test the publication bias, Funnel plots and Egger’s linear regression test was applied (Egger et al. 1997). All analyses were done with Stata software (version 8.2; StataCorp LP, College Station, TX), using two-sided P values.

Results

Characteristics of studies

There were 19 articles relevant to the search words, including two in manual search (Fig. 1). Nine of these studies met the present inclusion criteria, in which nine case–control studies with 10,746 cases and 9,158 controls regarding rs2294008 C > T polymorphism and five case–control studies with 6,080 cases and 4,824 controls regarding rs2976392 G > A polymorphism. We excluded 10 studies (five were not for gastric cancer, two were not for PSCA, one was review, one did not report detailed allele frequency data and one was duplicate of the previous publication). The characteristics of selected studies are summarized in Table 1. All studies were case–control studies, in which there were eight studies of Asian descendents, two studies of European descendents. Gastric cancer was diagnosed histologically or pathologically in most studies. Controls were mainly matched for sex and age, of which five were population based and five were hospital based. A classic polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay and TaqMan assay were conducted in four and two of the nine studies, respectively (Table 1). Besides, three studies investigated the interactions between two polymorphisms and environmental factors. The genotype distributions among the controls of all studies were not deviated from the HWE.

Fig. 1.

Fig. 1

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Articles identified with criteria for inclusion and exclusion

Table 1.

Characteristics of PSCA rs2294008 C > T and PSCA rs2976392 G > A polymorphisms in eligible studies included in this meta-analysis

PSCA rs2294008 C > T
First authors
(year)		 Country Ethnicity Source of controls Genotyping method Cases/controls
Lochhead (2011) Scotland European PB TaqMan 600/590
Song (2011) Korea Asian PB (Korean) PCR–RFLP 3,245/1,700
Zeng (2011) China Asian PB (Chinese) PCR–RFLP 460/549
Sala (2011) Spain European HB ND 409/1,515
Lu (2010) China Asian PB (Chinese) PCR–RFLP 1,023/1,069
Ou (2010) China Asian PB (Chinese) PCR-LDR 196/246
Matsuo (2009) Japan Asian HB (Japanese) TaqMan 708/708
Wu (2009) China Asian PB (Chinese) PCR–RFLP 1,710/995
Sakamoto (2008) Japan Asian HB (Japanese) Multiplex PCR 1,524/1,396
Asian HB (Korean) Multiplex PCR 871/390
PSCA rs2976392 G > A
First authors
(year)		 Country Ethnicity Source of controls Genotyping method Cases/controls
Lu (2010) China Asian PB (Chinese) PCR–RFLP 1,043/1,082
Ou (2010) China Asian PB (Chinese) PCR-LDR 196/246
Matsuo (2009) Japan Asian HB (Japanese) TaqMan 707/707
Wu (2009) China Asian PB (Chinese) PCR–RFLP 1,724/1,002
Sakamoto (2008) Japan Asian HB (Japanese) Multiplex PCR 1,525/1,397
Asian HB (Korean) Multiplex PCR 885/390
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PCR–RFLP polymerase chain reaction–restriction fragment length polymorphism; LDR ligase detection reaction; PB population-based; HB hospital-based; ND not determined

Quantitative synthesis

PSCA rs2294008 C > T. The frequency of T allele was not found to be statistically significant across different ethnicities (P = 0.608). The frequencies of T allele were 0.41 (95 % CI = 0.28–0.55) among Asian controls and 0.48 (95 % CI = 0.02–0.93) among European controls.

Overall, as shown in Table 2, the individuals carrying variant genotypes had an increased risk of gastric cancer in all genetic model, when all the eligible studies were pooled into the meta-analysis (TT vs. CC: OR = 1.75, 95 % CI = 1.40–2.20, P heterogeneity < 0.001; TC vs. CC: OR = 1.53, 95 % CI = 1.31–1.78, P heterogeneity < 0.001; TT/TC vs. CC: OR = 1.61, 95 % CI = 1.35–1.91, P heterogeneity < 0.001; TT vs. TC/CC: OR = 1.33, 95 % CI = 1.24–1.42, P heterogeneity = 0.186). In the stratified analysis by ethnicity, significantly increased risks of gastric cancer were detected in European and Asian populations in all genetic models (TT vs. CC: OR = 1.78, 95 % CI = 1.34–2.36, P heterogeneity < 0.001; TT/TC vs. CC: OR = 1.66, 95 % CI = 1.35–2.05, P heterogeneity < 0.001 for Asians and TT vs. CC: OR = 1.65, 95 % CI = 1.13–2.43, P heterogeneity = 0.079; TT/TC vs. CC: OR = 1.42, 95 % CI = 1.18–1.71, P heterogeneity = 0.113 for Europeans). In sources of controls, significant effects were observed in all genetic models except the individuals with genotype of TT versus TC/CC (OR = 1.14, 95 % CI = 0.98–1.32, P heterogeneity = 0.542) in population-based controls (Table 2).

Table 2.

Meta-analysis of the PSCA rs2294008 C > T polymorphism on gastric cancer risk

Variables n a TT versus CC TC versus CC TT/TC versus CC TT versus TC/CC
OR (95 % CI) P b OR (95 % CI) P b OR (95 % CI) P b OR (95 % CI) P b
Total 10 1.75 (1.40–2.20)c <0.001 1.53 (1.31–1.78)c <0.001 1.61 (1.35–1.91)c <0.001 1.33 (1.24–1.42) 0.186
Ethnicity
 Asian 8 1.78 (1.34–2.36)c <0.001 1.59 (1.33–1.91)c <0.001 1.66 (1.35–2.05)c <0.001 1.31 (1.22–1.42) 0.166
 European 2 1.65 (1.13–2.43)c 0.079 1.29 (1.06–1.57) 0.184 1.42 (1.18–1.71) 0.113 1.41 (1.18–1.68) 0.211
Source of controls
 Population-based 5 1.75 (1.60–1.92) 0.508 1.26 (1.15–1.40) 0.526 1.26 (1.15–1.39) 0.491 1.14 (0.98–1.32) 0.542
 Hospital-based 5 2.26 (1.72–2.97)c 0.001 1.84 (1.44–2.35)c 0.001 2.00 (1.55–2.59)c <0.001 1.39 (1.28–1.50) 0.384
Site
 Non-cardia versus cardia 4 1.57 (1.19–2.05) 0.189 1.18 (1.00–1.39) 0.371 1.24 (1.06–1.45) 0.123 1.43 (1.12–1.83) 0.426
Histology
 Diffuse versus intestinal 6 1.69 (1.26–2.29)c 0.081 1.29 (0.92–1.79)c <0.001 1.37 (0.99–1.89) <0.001 1.29 (1.13–1.49) 0.975
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aNumber of comparisons

b P value of Q-test for heterogeneity test

cRandom-effects model was used when P value for heterogeneity test <0.10; otherwise, fix-effects model was used

Specifically, stratifying by clinicopathologic characteristics of tumor location and histology, the pooled results showed that variation genotype had a higher risk on non-cardia compared with cardia gastric cancer (TT vs. CC: OR = 1.57, 95 % CI = 1.19–2.05, P heterogeneity = 0.189; TT/TC vs. CC: OR = 1.24, 95 % CI = 1.06–1.45, P heterogeneity = 0.123; TT vs. TC/CC: OR = 1.43, 95 % CI = 1.12–1.83, P heterogeneity = 0.426) as same as diffused compared with intestinal gastric cancer (TT vs. CC: OR = 1.69, 95 % CI = 1.26–2.29, P heterogeneity = 0.081; TT vs. TC/CC: OR = 1.29, 95 % CI = 1.13–1.49, P heterogeneity = 0.975) (Table 2).

PSCA rs2976392 G > A. An increased risk of gastric cancer was observed in all genetic models (AA vs. GG: OR = 1.81, 95 % CI = 1.21–2.72, P heterogeneity < 0.001; AG vs. GG: OR = 1.62, 95 % CI = 1.24–2.12, P heterogeneity < 0.001; AA/AG vs. GG: OR = 1.69, 95 % CI = 1.24–2.13, P heterogeneity < 0.001; AA vs. AG/GG: OR = 1.36, 95 % CI = 1.24–1.50, P heterogeneity = 0.111; Table 3). Both population-based studies and hospital-based studies were associated with a significantly increased risk of the gastric cancer, but not for homozygote comparison (AA vs. GG: OR = 1.15, 95 % CI = 0.93–1.42, P heterogeneity = 0.890) and recessive model (AA vs. AG/GG: OR = 1.04, 95 % CI = 0.84–1.28, P heterogeneity = 0.984).

Table 3.

Meta-analysis of the PSCA rs2976392 G > A polymorphism on gastric cancer risk

Variables n a AA versus GG AG versus GG AA/AG versus GG AA versus AG/GG
OR (95 % CI) P b OR (95 % CI) P b OR (95 % CI) P b OR (95 % CI) P b
Total 6 1.81 (1.21–2.72)c <0.001 1.62 (1.24–2.12)c <0.001 1.69 (1.24–2.31)c <0.001 1.36 (1.24–1.50) 0.111
Source of controls
Population-based 3 1.15 (0.93–1.42) 0.890 1.24 (1.11–1.39) 0.255 1.23 (1.10–1.37) 0.278 1.04 (0.84–1.28) 0.984
Hospital-based 3 2.77 (2.31–3.33) 0.662 2.24 (1.88–2.67) 0.707 2.47 (2.09–2.92) 0.690 1.47 (1.32–1.65) 0.825
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aNumber of comparisons

b P value of Q-test for heterogeneity test

cRandom-effects model was used when P value for heterogeneity test <0.10; otherwise, fix-effects model was used

Test of heterogeneity

For PSCA rs2294008 C > T, there was significant heterogeneity for homozygote comparison (TT vs. CC: P heterogeneity < 0.001), heterozygote comparison (TC vs. CC: P heterogeneity < 0.001) and dominant model (TT/TC vs. CC: P heterogeneity < 0.001) except recessive model (TT vs. TC/CC: P heterogeneity = 0.186). Then, we assessed the source of heterogeneity for homozygote comparison (TT vs. CC) by ethnicity, source of controls and sample size (subjects >400 in both cases and controls). As a result, source of controls (P < 0.001), but not the ethnicity (P = 0.608) or the sample size (P = 0.588), contributed to substantial heterogeneity. For PSCA rs2976392 G > A, heterogeneity between studies was observed in all comparisons except recessive model (TT vs. TC/CC, P heterogeneity = 0.111). As above, source of controls was found to be associated with substantial heterogeneity (P < 0.001) for dominant model (AA/AG vs. GG), instead of the sample size (P = 0.830).

Publication bias

Begg’s funnel plot and Egger’s test were performed to assess the publication bias of the currently available literatures. As shown in Fig. 2, the shape of the funnel plots did not reveal any evidence for obvious asymmetry in all comparison models. Then, the Egger’s test was used to provide statistical evidence for funnel plot symmetry. The results still did not show any evidence of publication bias (t = 1.50, P = 0.173 for rs2294008; TT/TC vs. CC and t = 0.64, P = 0.558 for rs2976392 AA/AG vs. GG).

Fig. 2.

Fig. 2

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Begg’s funnel plot for publication bias test. a PSCA rs2294008 C > T: TT/TC versus CC. b PSCA rs2976392 G > A: AA/AG versus GG. Each point represents a separate study for the indicated association. Log [or], natural logarithm of OR. Horizontal line mean effect size

Discussion

The association between two polymorphisms in PSCA and gastric cancer risk was explored in the present meta-analysis, including 10,746 cases and 9,158 controls from nine published case–control studies. The variant genotypes of PSCA rs2294008 C > T and PSCA rs2976392 G > A polymorphisms were associated with significantly increased risk of gastric cancer. Given the important roles of PSCA in the regulation of cell proliferation, it is biologically plausible that genetic variations of the PSCA polymorphisms may modulate the risk of gastric cancer. PSCA is involved in the cell-proliferation inhibition and/or cell-death induction activity (Sakamoto et al. 2008), acting as a tumor suppressor. PSCA mRNA is highly abundant in gastric mucosa but undetectable in gastric tumor tissues (Bahrenberg et al. 2000). Recently, GWAS by Sakamoto et al. had confirmed that PSCA rs2294008 T allele and PSCA rs2976392 A allele were associated with the diffuse-type gastric cancer risk among Japanese and Korean populations, which were replicated in Japanese and validated in different Asian populations and Europeans (Matsuo et al. 2009; Wu et al. 2009; Lochhead et al. 2011; Song et al. 2011). Furthermore, they demonstrated that substitution of the C allele with the risk allele T at rs2294008 reduced transcriptional activity of an upstream fragment of PSCA, thus increasing the susceptibility of diffuse-type gastric cancer. The rs2976392 G > A was in strong linkage disequilibrium (LD) with the rs2294008 C > T (Sakamoto et al. 2008). The functional relevance of rs2976392 G > A was similar to the rs2294008 C > T, while not identified yet (Wu et al. 2009).

It has been known that gastric cancer could be further classified as intestinal and diffused subtypes by histology, cardia and non-cardia subtypes by tumor location (Lauren 1965). We found that rs2294008 T allele could significantly increase the risk of non-cardia and diffused gastric cancer compared with cardia and intestinal gastric cancer, respectively (Sakamoto et al. 2008; Wu et al. 2009; Lochhead et al. 2011). Recently, one GWAS in Chinese reported that rs2294008 polymorphism was associated with gastric non-cardia cancer, which was consistent with our results (Abnet et al. 2010). However, stratifying analysis by tumor location and histology of rs2976392 G > A was not mentioned in most studies.

In constantly, Zeng et al. observed PSCA rs2294008 was significantly associated with intestinal type gastric cancer in Chinese, which may due to the frequency of the variant T allele in the Chinese population lower than that in both Korean and Japanese populations. Similar results were observed in the present study. The frequencies of T and A allele of rs2294008 and rs2976392 in the Chinese population were 0.273 and 0.270, respectively, which were considerably lower than those in the Japanese and Korean populations, in line with recent reports (Wu et al. 2009; Lu et al. 2010). The striking difference in the distribution of PSCA rs2294008T or rs2976392A allele frequencies among the Chinese, Korean and Japanese populations, which might reflect the history of human migration, suggested that if these SNPs play a role in gastric carcinogenesis, their population attributable risk for gastric cancer in these three Asian populations would be different and less important in the Chinese population when environmental factors for the cancer are disregarded (Wu et al. 2009). However, only four studies reported the gastric cancer risk in the Chinese population, and the inconclusive result in our meta-analysis need to be validated in more studies. For there was not enough information of the interaction between SNPs and the environmental factors such as tobacco smoking, alcohol consumption and Helicobacter pylori (H. pylori) infection, it was not included in the present meta-analysis.

To identify the source of heterogeneity, we stratified the studies according to ethnicity, cancer type and source of control. We found that the source of heterogeneity was from source of controls. Hospital-based controls might not stand for the study population or the general population, particularly when the genotypes under investigation were associated with the disease-related conditions, suggesting that using proper and representative population-based control subjects was very important in reducing biases in such genotype association studies.

Some limitations of the meta-analysis should be mentioned. Firstly, lacking of the original data of the reviewed studies limited our further evaluation of the potential interactions, such as the interactions between PSCA polymorphisms and H. pylori, smoking and drinking, respectively, because gene-environment interactions and even different polymorphic loci of the same gene may modulate cancer risk. Secondly, our result was based on unadjusted estimates, while a more precise analysis needs to be conducted if individual data are available, which would allow for an adjusted estimate by age and sex. However, we also had strengths in the present study. Substantial number of cases and controls were pooled from different studies, which significantly increased the statistical power of the analysis; the quality of case–control studies included in the present meta-analysis was satisfactory and met our selection criterion, and publication bias was not detected, indicating that the whole pooled result should be unbiased.

In conclusion, our meta-analysis suggested that PSCA rs2294008 C > T and rs2976392 G > A polymorphisms may contribute to the gastric cancer risk, particularly for gastric cancer with non-cardia or diffused. Similar association was found in both Asians and Europeans. Therefore, additional larger studies of many ethnic groups and other cancers were warranted to validate our findings. Moreover, investigations of the combined effects of gene and environment should be used to provide the better more comprehensive understanding of the association between the PSCA polymorphisms and gastric cancer risk.

Acknowledgments

This study was partly supported by National Natural Science Foundation of China (30972444 and 81102089), the Key Program of Natural Science Foundation of Jiangsu Province (BK2010080), Natural Science Foundation of Jiangsu Province (BK2011773 and BK2011775), the Key Program for Basic Research of Jiangsu Provincial Department of Education (11KJB330002), Jiangsu Provincial Graduates Innovative Project (CX10B-346Z), the Qin Lan Project of Jiangsu Provincial Department of Education, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Conflict of interest

The authors declare no conflicts of interest.

Footnotes

Danni Shi, Shizhi Wang and Dongying Gu contribute equally to this work.

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