Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk.
ABSTRACT: Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r(2) = 0.02, D' = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06-1.17, P = 5.8 × 10(-5)] for rs2294008 and OR = 1.07 (95% CI = 1.02-1.13, P = 9.7 × 10(-3)) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08-1.41, P = 1.8 × 10(-3)) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors.
Project description:We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
Project description:Prostate stem cell antigen (PSCA) was originally identified as a gene that is overexpressed in prostate cancer, and correlates with prostate cancer progression and prognosis. Recently, a significant association has been identified between the PSCA rs2294008 (C>T) polymorphism and the risk of developing bladder cancer. Therefore, the present study investigated the different expression levels of PSCA mRNA in transitional cell carcinoma (TCC) of the bladder and normal bladder tissue. Furthermore, the association between PSCA mRNA expression levels in TCC and different rs2294008 (C>T) genotypes and various clinicopathological features, including tumor stage and grade, were evaluated. Reverse transcription-quantitative polymerase chain reaction was performed on 80 TCC samples and 38 samples of normal bladder urothelium from TCC patients who underwent transurethral resection of bladder tumor or radical cystectomy at the Beijing Friendship Hospital (Beijing, China) between September 2010 and May 2011. Genomic DNA was extracted from tumor tissue and sequenced to determine the rs2294008 (C>T) genotype. PSCA mRNA expression was detected in all samples (100%); however, tumor samples exhibited significantly higher PSCA expression levels compared with the normal urothelium samples (P=0.038). PSCA mRNA expression was positively correlated with the histological grade of the tumor (G1-2 vs. G3; P=0.001); however, no significant difference was detected between patients with superficial (Ta or T1) and muscle-invasive (≥pT2) tumors (P=0.250). Thus, PSCA mRNA expression levels were associated with TCC and tumor histological grade, but not the tumor stage. Additionally, PSCA mRNA expression levels were significantly higher in T allele carriers compared with CC homozygous patients (P=0.001), indicating that the presence of the T allele may increase PSCA mRNA expression. Therefore, rs2294008 (C>T) may be associated with the biological properties of TCC and, thus, future research should focus on the physiological function of PSCA and the mechanism of rs2294008.
Project description:BACKGROUND: Previous studies suggested genetic variations in PSCA (prostate stem cell antigen) may confer the susceptibility of cancer. Many case-control studies have reported the relationship between PSCA rs2294008 C > T polymorphism and cancer, especially gastric cancer and bladder cancer. However, the results are inconsistent. This meta-analysis is aimed at evaluating the association of rs2294008 polymorphism with cancer risk. METHODS: The databases of PubMed, ISI Web of Knowledge, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for related publications. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations. Fixed models were used when heterogeneity among studies was not detected, otherwise the random model was used. RESULTS: Twenty-six studies from 24 articles with 30,050 multiple cancer cases and 51,670 controls were pooled into this meta-analysis. The results showed that the rs2294008 polymorphism was associated with increased cancer risk in any genetic model (T vs C, OR: 1.18, 95% CI: 1.08-1.28; TT vs CC, OR: 1.36, 95% CI: 1.14-1.62; TC vs CC, OR: 1.29, 95% CI: 1.17-1.44; TT + TC vs CC, OR: 1.32, 95% CI: 1.18-1.49; TT vs TC + CC, OR: 1.15, 95% CI: 1.02-1.30). In stratified analysis by cancer type, we found that the T allele had a significant high risk of gastric and bladder cancer, but not in other cancers. In subgroup analysis by ethnicity, increased cancer risk was found in both Asians and Caucasians. CONCLUSION: Our study suggested that the PSCA rs2294008 C > T polymorphism is a risk factor for cancer, especially in gastric and bladder cancer.
Project description:Multiple studies have investigated the association of gene variant of Deleted in colorectal carcinoma (DCC) and Prostate Stem cell antigen (PSCA) with various cancer susceptibility; however, the results are discrepant. Since SNPs are emerging as promising biomarker of cancer susceptibility, here, we aimed to execute a meta-analysis of DCC (rs714 A > G) and PSCA (rs2294008 C > T, rs2976392 G > A) polymorphism to demonstrate the more accurate strength of these associations. We followed a rigorous inclusion/exclusion criteria and calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Overall, the pooled analysis showed that the DCC rs714 conferred increased risk of cancer only in Asians (AA vs. GG: OR = 1.86, p ? 0.0001; AG vs. GG: OR = 1.43, p = 0.005; GA + AA vs. GG: OR = 1.66, p ? 0.0001; AA vs. GG + GA; OR = 1.52, p ? 0.004, A vs. G allele: OR = 1.41, p ? 0.0001). PSCA rs2294008 was associated with increased overall cancer risk (TT vs. CC: OR = 1.28, p = 0.002; CT vs. CC: OR = 1.21, p ? 0.0001; CT + TT vs. CC: OR = 1.24, p ? 0.0001; TT vs. CC + CT; OR = 1.17, p ? 0.005, T vs. C allele: OR = 1.16, p ? 0.0001); however, in stratified analysis this association was limited only to gastric and bladder cancer and the strength was more prominent in Asians. In contrast, the PSCA rs2976392 SNP did not modulate the cancer risk. Therefore, we concluded that rs714 and rs2294008 polymorphism may represent a potential genetic biomarker for cancer risk in Asians and gastric as well as bladder cancer, respectively. However, since our study is limited to Asians and cancer types, further larger studies involving other cancers and/or population, gene-environment interactions and the mechanism of DCC and PSCA gene deregulation are desired to define the role of genotype with overall cancer risk.
Project description:SNPs in the Prostate Stem Cell Antigen (PSCA) gene have been found associated with gastric cancer (GC) risk in a genome-wide association study. This association has been replicated in several populations. In this study we assessed the impact of PSCA genotype on the risk of advanced gastric precancerous lesions and GC. We used baseline gastric histopathology data and DNA from frozen gastric biopsies of 2045 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela, and 180 cases of GC from the same area. We analyzed 3 SNPs in the PSCA gene (rs2294008, rs9297976 and rs12155758) which were previously found to be associated with GC risk in Europeans. The T allele of rs2294008 was found to be associated with a higher prevalence of atrophic gastritis (OR = 1.44; 95% CI 1.03-2.01 for the dominant model) and intestinal metaplasia (OR = 1.50; 95% CI 1.13-1.98 for the dominant model). We also confirmed the association with higher risk of gastric cancer (OR = 2.34; 95% CI 1.36-4.01 for the allele carriers). SNP rs12155758 was not associated with risk of gastric preneoplastic lesions, but we confirmed its association with higher GC risk (OR 1.95; 95% CI 1.29-2.97 for dominant model). We tested the relevance of the presence of the Helicobacter pylori cagA gene, which is known to increase the risk of more severe gastric lesions, but we did not find any clearcut interaction with PSCA SNPs in defining risk of gastric precancerous lesions or cancer.
Project description:Previous studies have investigated the associations between the two polymorphisms (prostate stem cell antigen (PSCA) rs2294008 C/T and c-MYC rs9642880 G/T) and bladder cancer (BC) risk. However, the results are inconsistent. We therefore carried out a meta-analysis to estimate the relationship between PSCA/c-MYC polymorphisms and BC risk. We searched PubMed up to November 2014 to identify potentially eligible literatures. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations, the data were further stratified by ethnicity. Heterogeneity was evaluated by Q test and I(2) statistics. Begg's funnel plot and Egger's test were used to assess the publication bias. 11 studies from 9 articles were identified, including a total of 16,814 cancer cases and 52,868 case-free controls. We found a significant association between PSCA rs2294008 polymorphism and BC risk (the allele contrast model: OR = 1.14, 95% CI = 1.11-1.18; homozygote comparison: OR = 1.28, 95% CI = 1.20-1.37; heterozygote comparison: OR = 1.23, 95% CI = 1.17-1.30; dominant model: OR = 1.25, 95% CI = 1.19-1.31 and recessive model: OR = 1.13, 95% CI = 1.07-1.20). Moreover, a significant increased risk of BC was confirmed both in Caucasian and in Asians. For c-MYC rs9642880 polymorphism, significant increased BC risk was detected under the following genetic models (the allele contrast model: OR = 1.20, 95% CI = 1.13-1.27; homozygote comparison: OR = 1.37, 95% CI = 1.21-1.55; heterozygote comparison: OR = 1.20, 95% CI = 1.09-1.32; dominant model: OR = 1.25, 95% CI = 1.14-1.37 and recessive model: OR = 1.26, 95% CI = 1.13-1.40). Further stratified analysis by ethnicity also observed the same results. This meta-analysis suggested that PSCA rs2294008 and c-MYC rs9642880 polymorphisms may increase the BC risk. Further studies are needed to clarify the effects.
Project description:Recently, three genome-wide association studies have identified the PSCA (prostate stem cell antigen) rs2294008 polymorphism (C?>?T) associated with susceptibility to gastric cancer, bladder cancer, and duodenal ulcers, highlighting its critical role in disease pathogenesis. Given PSCA is reported to be overexpressed in cervical cancer and the rs2294008 can influence PSCA transcription, we aimed to determine the role of rs2294008 in susceptibility to cervical cancer. The genotyping was performed in the 1126 cases and 1237 controls. Our results showed the rs2294008 TT genotype significantly associated with a reduced risk of cervical cancer (adjusted OR?=?0.55, 95%?CI?=?0.38-0.79; recessive model). Stratified analyses revealed that the association was restricted to the subgroups of age?>?49 years, parity ? 1, abortion and early-stage cervical cancer. Immunohistochemistry assay showed the individuals carrying the TT genotype having lower PSCA expression than those with CC/CT genotypes. In summary, the PSCA rs2294008 polymorphism may serve as a biomarker of cervical cancer, particularly of early-stage cervical cancer.
Project description: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.
Project description:Published data on the association between PSCA rs2294008 polymorphism and cancer risk have implicated inconclusive results. To determine the relationship and to precisely assess the effect size estimate of the association, we performed a meta-analysis.We searched published literature in Embase and PubMed databases using the search terms "PSCA", "prostate stem cell antigen", "variants", "polymorphism", "polymorphisms", and "cancer". A total of 21 eligible articles were retrieved, with 27, 197 cancer cases and 48, 237 controls.On the whole, we found the association between PSCA rs2294008 polymorphism and cancer risk was statistically significant: TT vs CC: OR = 1.18, 95% CI, 1.10 to 1.27; TT + CT vs CC: OR = 1.08, 95% CI, 1.05 to 1.10; TT vs CT + CC: OR = 1.14, 95% CI, 1.07 to 1.21; T vs C: OR = 1.10, 95% CI, 1.06 to 1.14; CT vs CC: OR = 1.10, 95% CI, 1.06 to 1.13. Stratified analyses in cancer type and ethnicity showed similar results.Based on the statistical evidence, we can draw a conclusion that the rs2294008 polymorphism of PSCA gene is likely to play a role in cancer carcinogenesis, especially in gastric cancer and bladder cancer.
Project description:OBJECTIVE:Number of studies have been performed to evaluate the relationship between prostate stem cell antigen (PSCA) variation rs2294008 and bladder cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association. METHODS:Pubmed, Web of science, Embase, China biology medical literature database (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang and Weipu databases were searched before June 30, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0. RESULTS:Ten studies involved 14,021 cases and 26,871 controls. Overall, significant association was observed between the PSCA gene variant rs2294008 polymorphism and bladder cancer (T vs C: OR?=?1.16, 95%CI?=?1.12-1.20; TT vs CC: OR?=?1.32, 95%CI?=?1.24-1.41; TT vs CT+CC: OR?=?1.15, 95%CI?=?1.09-1.22; TT+CT vs CC: OR?=?1.27, 95%CI?=?1.21-1.34). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR?=?1.23, 95%CI?=?1.15-1.31) and Caucasians (T vs C: OR?=?1.14, 95%CI?=?1.10-1.18). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. CONCLUSION:Our meta-analysis supports that the PSCA gene variant rs2294008 polymorphism might contribute to individual susceptibility to bladder cancer.