Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.

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.

PURPOSE: Half of the world's gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have revealed susceptibility genes associated with gastric cancer, no GWASs have been conducted in the Korean population, which has the highest incidence of gastric cancer.
Materials and Methods: We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and 3,693 healthy controls.
RESULTS: We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastriccancer-susceptibility gene in a Korean population, with genome-wide significance and an odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage disequilibrium with rs2294008 was also found, indicating an association with susceptibility. Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to 0.57). The effect of the PSCA gene on gastric cancer was more prominent in the female population and for diffuse type gastric cancer.
CONCLUSION: Our result confirmed that the PSCA gene may be the most important susceptibility gene for gastric cancer risk in a Korean population.

The aim of this study is to make a comparative evaluation on association of PSCArs2294008 C/T polymorphism with the risk of bladder cancer in Bai, Dai, and Han people in China. A potential mechanism of the T allele risk was also investigated. T allele increased the occurring risk of bladder cancer in Han (OR 1.34; 95% CI 1.17-1.69), Dai, (OR 1.33; 95% CI 1.12-1.70), and Bai (OR 1.14; 95% CI 1.08-1.57) people. T genotype was also observed to associate with invasive bladder cancer in all the three populations (Bai, OR 1.15, 95% CI 1.07-1.87; Dai, OR 1.17, 95% CI 1.05-2.23; Han, OR 1.22, 95% CI 1.10-2.09). PSCA m-RNA levels in T genotype bladder cancer tissues were significantly lower than those in C genotype. An enhancement of PSCA m-RNA level by over-expressing C or T genotype in bladder cancer cells both decreased the cell proliferation and migration, but not affected cell cycle. The increased cell apoptasis due to the over-expression of the two variants was observed. Those change of cell proliferation, migration, and apoptasis was more remarkable in over-expressed C genotype cells than those in over-expressed T genotype. T genotype was genetically high risk to the occurrence of bladder cancer. The decreased PSCA m-RNA levels were involved in the progress of bladder cancer. T allele takes more responsibility for PSCA m-RNA down-regulation to promote cell proliferation and migration and hinder cell apoptasis, thus leading to a higher risk.

BACKGROUND: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.
OBJECTIVE: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.
DESIGN, SETTING, AND PARTICIPANTS: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.
RESULTS AND LIMITATIONS: Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p=0.061), PFS (HR 0.50; p=0.090), and OS (HR 0.28; p=0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25-0.92; p=0.027), PFS (HR 0.52, 95% CI 0.28-0.98; p=0.044), and OS (HR 0.34, 95% CI 0.12-0.99; p=0.048), but not in men with non-BRCA/ATM germline mutations (all p>0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n=9) with BRCA/ATM mutations.
CONCLUSIONS: Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.
PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) is important for selecting patients for targeted treatments. We present, for the first time, results on gene expression profiling of CTCs isolated in vivo from high-risk prostate cancer (PCa) patients compared with CTC detected by 3 protein-based assays-CellSearch
METHODS: EpCAM-positive CTCs were isolated in vivo using the CellCollector from 108 high-risk PCa patients and 36 healthy volunteers. For 27 patients, samples were available before and after treatment. We developed highly sensitive multiplex RT-qPCR assays for 14 genes (
RESULTS: We observed high heterogeneity in gene expression in the captured CTCs for each patient. At least 1 marker was detected in 74 of 105 patients (70.5%), 2 markers in 45 of 105 (40.9%), and 3 markers in 16 of 105 (15.2%). Epithelial markers were detected in 31 of 105 (29.5%) patients, EMT markers in 46 of 105 (43.8%), and stem cell markers in 15 of 105 (14.3%) patients. EMT-marker positivity was very low before therapy (2 of 27, 7.4%), but it increased after therapy (17 of 27, 63.0%), whereas epithelial markers tended to decrease after therapy (2 of 27, 7.4%) compared with before therapy (13 of 27, 48.1%). At least 2 markers were expressed in 40.9% of patients, whereas the positivity was 19.6% for CellSearch, 38.1% for EPISPOT, and 43.8% for CellCollector-based IF-staining.
CONCLUSIONS: The combination of in vivo CTC isolation with downstream RNA analysis is highly promising as a high-throughput, specific, and ultrasensitive approach for multiplex liquid biopsy-based molecular diagnostics.

Eleven high-evidence single-nucleotide polymorphisms (SNPs) at nine loci for gastric cancer (GC) risk were reported, but their associations with survival remain unknown. In this study, we examined associations between SNP and GC survival by anatomic location and histology among 1147 incident cases from the Shanxi Upper Gastrointestinal Genetics Project. We further examined whether SNPs were expression quantitative trait loci in normal and tumor gastric tissues, and whether tumor versus normal somatic mRNA differences in 126 cases were associated with survival. No SNPs were associated with GC survival overall. However, subtype-specific associations were observed for gastric cardia adenocarcinomas at MUC1/TRIM46/1q22 rs2070803 [HRAA versus GA+GG = 2.16; 95% confidence interval (CI) = 1.24-3.78; P = 0.0068] and LTA/TNF/6p21.33 rs1799724 (HRTT+CT versus CC = 1.30; 95% CI = 1.07-1.57; P = 0.0077), and for diffuse-type GC at PSCA/8q24.3 rs2294008 (HRTT versus CT+CC = 1.99; 95% CI = 1.33-2.97; P = 7.8E-04). Rs2294008T was a cis-expression quantitative trait loci for PSCA, upregulating mRNA in normal gastric (β = 0.60; P = 5.7E-21) and GC (β = 0.30; P = 0.0089) tissues. Cases in the highest quartile (the smallest downregulation of tumor PSCA) had shortest survival than cases with the most downregulated PSCA (median survival of 0.47 years in the highest quartile versus 3.73 years in the lowest quartile; hazard ratio = 9.70; 95% CI = 2.46-38.4; P = 0.0012). Less striking effects for mRNA levels were observed for MTX1 at 1q22 in gastric cardia adenocarcinoma and for JRK at 8q24.3 in diffuse GC. Our results suggest three high-evidence GC risk loci have prognostic importance in GC subtypes. Future studies in well-characterized independent populations are warranted to validate our findings and further investigate the clinical utility of these variants in predicting GC prognosis.

BACKGROUND: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. We previously reported that PSCA involved in proliferation and invasion of PCa cells, however, the underlying mechanisms are unknown. In this study, we aimed to explore the regulating role of PSCA gene expression in interleukin-6 (IL-6) autocrine of PCa cells.
METHODS: The stable knockdown-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa DU145 and PC-3M cells. The effects of PSCA overexpression or knockdown were determined in proliferation, invasion, and metastasis assays. The effect of PSCA on the expression and secretion of IL-6 was evaluated by immunoblotting and ELISA. Subcellular localization and expression pattern of PSCA and IL-6 protein were examined by immunohistochemistry. Its clinical significance was statistically analyzed.
RESULTS: The results showed that stable knockdown of PSCA delayed proliferation, migration, and invasion while overexpressing PSCA enhanced the proliferation, migration, and invasion in vitro and the lung metastasis in vivo of PCa cells. Importantly, the PSCA involved in the IL-6 secretion and positively regulated p38/NF-κB/IL-6 signaling, leading to enhanced PCa cell invasion and metastasis. Both the expression of PSCA and IL-6 were significantly associated with poor biochemical recurrence-free survival of patients with PCa. PSCA protein expression showed a prognostic value in overall survival as indicated by Kaplan-Meier analysis.
CONCLUSIONS: These results indicate that PSCA regulates the expression and secretion of IL-6 in human PCa cells through p38/NF-κB signaling pathways. PSCA may be a potential diagnostic marker and therapeutic target for PSCA-positive PCa.

PURPOSE: Invasive micropapillary carcinoma (IMPC) of the breast has distinct histological features and molecular genetic profiles. Gains/amplifications of 8q24 are found associated with IMPC. Although the prostate stem cell antigen (PSCA) gene is located at chromosome 8q24, and found over-expressed in prior studies, its prognostic values and biological significance in IMPC have not been well studied.
METHODS: Fluorescence in situ hybridization (FISH) was used to assess the frequencies of PSCA copy number gains in IMPC, invasive ductal carcinoma of no special type (IDC-NST), and invasive lobular carcinoma (ILC) samples. The protein expression levels of PSCA were examined in 56 IMPC, 72 IDC-NST, and 56 ILC samples using immunohistochemical analysis.
RESULTS: PSCA gene amplification was detected in 45.2% (14/31) of the IMPC, 28.1% (9/32) of the IDC-NST, and none (0/25) of the ILC. PSCA protein expression was observed in 58.9% (33/56), 40.3% (29/72), and 3.6% (2/56) of IMPC, IDC-NST, and ILC samples, respectively. The concordant rate of the immunohistochemistry and FISH data was 85.2%. PSCA gene amplification highly correlated with its protein overexpression (rs = 0.687, P < 0.001), suggesting that gene amplification is an important mechanism involved in PSCA overexpression. Our univariate analysis showed that the patients with PSCA-positive IMPC had a decreased disease-free survival (DFS) compared to PSCA-negative IMPC patients (P = 0.003). Our multivariate analysis confirmed the worse DFS in PSCA-positive IMPC patients (P = 0.022).
CONCLUSIONS: Our results indicate that PSCA may be an attractive target in the 8q24 amplicon and that it may serve as a molecular marker of metastasis and recurrence in IMPC. The differential expression of PSCA may be associated with cell adhesion. Detection of PSCA protein and gene amplification may help manage and predict the prognosis of IMPC patients.

Integrative analyses of several omics data are emerging. The data are usually generated from the same source material (i.e., tumor sample) representing one level of regulation. However, integrating different regulatory levels (i.e., blood) with those from tumor may also reveal important knowledge about the human genetic architecture. To model this multilevel structure, an integrative-expression quantitative trait loci (eQTL) analysis applying two-stage regression (2SR) was proposed. This approach first regressed tumor gene expression levels with tumor markers and the adjusted residuals from the previous model were then regressed with the germline genotypes measured in blood. Previously, we demonstrated that penalized regression methods in combination with a permutation-based MaxT method (Global-LASSO) is a promising tool to fix some of the challenges that high-throughput omics data analysis imposes. Here, we assessed whether Global-LASSO can also be applied when tumor and blood omics data are integrated. We further compared our strategy with two 2SR-approaches, one using multiple linear regression (2SR-MLR) and other using LASSO (2SR-LASSO). We applied the three models to integrate genomic, epigenomic, and transcriptomic data from tumor tissue with blood germline genotypes from 181 individuals with bladder cancer included in the TCGA Consortium. Global-LASSO provided a larger list of eQTLs than the 2SR methods, identified a previously reported eQTLs in prostate stem cell antigen (PSCA), and provided further clues on the complexity of APBEC3B loci, with a minimal false-positive rate not achieved by 2SR-MLR. It also represents an important contribution for omics integrative analysis because it is easy to apply and adaptable to any type of data.

Gene-environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome-wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene-environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele-specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.

The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.

BACKGROUND: Detection and localization of genomic alterations and breakpoints are crucial in cancer research. The purpose of this study was to investigate, in a methodological and biological perspective, different female, hormone-dependent cancers to identify common and diverse DNA aberrations, genes, and pathways.
METHODS: In this work, we analyzed tissue samples from patients with breast (n = 112), ovarian (n = 74), endometrial (n = 84), or cervical (n = 76) cancer. To identify genomic aberrations, the Circular Binary Segmentation (CBS) and Piecewise Constant Fitting (PCF) algorithms were used and segmentation thresholds optimized. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was applied to the segmented data to identify significantly altered regions and the associated genes were analyzed by Ingenuity Pathway Analysis (IPA) to detect over-represented pathways and functions within the identified gene sets.
RESULTS AND DISCUSSION: Analyses of high-resolution copy number alterations in four different female cancer types are presented. For appropriately adjusted segmentation parameters the two segmentation algorithms CBS and PCF performed similarly. We identified one region at 8q24.3 with focal aberrations that was altered at significant frequency across all four cancer types. Considering both, broad regions and focal peaks, three additional regions with gains at significant frequency were revealed at 1p21.1, 8p22, and 13q21.33, respectively. Several of these events involve known cancer-related genes, like PPP2R2A, PSCA, PTP4A3, and PTK2. In the female reproductive system (ovarian, endometrial, and cervix [OEC]), we discovered three common events: copy number gains at 5p15.33 and 15q11.2, further a copy number loss at 8p21.2. Interestingly, as many as 75% of the aberrations (75% amplifications and 86% deletions) identified by GISTIC were specific for just one cancer type and represented distinct molecular pathways.
CONCLUSIONS: Our results disclose that some prominent copy number changes are shared in the four examined female, hormone-dependent cancer whereas others are definitive to specific cancer types.

Risk assessment and treatment choice remains a challenge in early non-small-cell lung cancer (NSCLC). The aim of this study was to identify novel genes involved in the risk of early relapse (ER) compared to no relapse (NR) in resected lung adenocarcinoma (AD) patients using a combination of high throughput technology and computational analysis. We identified 18 patients (n.13 NR and n.5 ER) with stage I AD. Frozen samples of patients in ER, NR and corresponding normal lung (NL) were subjected to Microarray technology and quantitative-PCR (Q-PCR). A gene network computational analysis was performed to select predictive genes. An independent set of 79 ADs stage I samples was used to validate selected genes by Q-PCR.From microarray analysis we selected 50 genes, using the fold change ratio of ER versus NR. They were validated both in pool and individually in patient samples (ER and NR) by Q-PCR. Fourteen increased and 25 decreased genes showed a concordance between two methods. They were used to perform a computational gene network analysis that identified 4 increased (HOXA10, CLCA2, AKR1B10, FABP3) and 6 decreased (SCGB1A1, PGC, TFF1, PSCA, SPRR1B and PRSS1) genes. Moreover, in an independent dataset of ADs samples, we showed that both high FABP3 expression and low SCGB1A1 expression was associated with a worse disease-free survival (DFS).Our results indicate that it is possible to define, through gene expression and computational analysis, a characteristic gene profiling of patients with an increased risk of relapse that may become a tool for patient selection for adjuvant therapy.

The prostate stem cell antigen (PSCA) gene, which encodes a prostate-specific antigen (PSA), was identified as a gene involved in cell adhesion and proliferation. The associations between the PSCA rs2294008 and rs2976392 single nucleotide polymorphisms (SNPs) and gastric cancer (GCa) susceptibility were still controversial. To derive a more precise estimation of the associations, we conducted a case-control study of 1,124 cases and 1,192 controls in an eastern Chinese population. We found that the rs2294008T variant genotypes were associated with an increased GCa risk in this study population (CT vs CC, OR=1.59, 95% CI=1.33-1.89 and CT+TT vs CC, OR=1.38, 95% CI=1.17-1.62). For SNP rs2976392, the variant A genotypes were also associated with an increased GCa risk (AG vs GG, OR=1.61, 95% CI=1.35-1.91 and AG+AA vs GG, OR=1.47, 95% CI=1.25-1.74). The results were further validated by a meta-analysis. In conclusion, the results indicated that the PSCA rs2294008 T and rs2976392 A alleles were low-penetrate risk factors for GCa in this study population. However, large and well-designed studies are warranted to validate our findings.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. By high-throughput transcriptome sequencing (RNA-Seq) profiling of three pairs of primary ESCCs and their corresponding non-tumorous tissues, we identified that prostate stem cell antigen (PSCA), a gene that encodes a glycosylphosphatidylinositol-anchored protein, is significantly downregulated in ESCC. Here, we reported decreased expression of PSCA in 188/218 (86.2%) of primary ESCC cases and was negatively regulated by its transcription factor sex-determining region Y-box5 that was significantly associated with the poor differentiation (P = 0.003), increased lymph node metastasis (P < 0.0001), advanced stage (P = 0.007), and disease-specific survival (P < 0.0001), but not associated with the recently reported transcrible rs2294008 (C > T) polymorphism in ESCC. Functional studies showed that PSCA could arrest cell cycle progression and promote cell differentiation independent of the start codon polymorphism. Further mechanistic studies revealed that retinoblastoma 1-inducible coiled-coil 1 (RB1CC1), a key signaling node to regulate cellular proliferation and differentiation, interacted specifically with PSCA in ESCC cells. Binding of PSCA and RB1CC1 in cytoplasm resulted in stabilization and translocation of RB1CC1 into nucleus, thereby activating key factors involved in cell cycle arrest and differentiation. Collectively, our data provide a novel molecular mechanism for the tumor suppressor role of PSCA and may help design effective therapy targeting PSCA-RB1CC1 pathway to control esophageal cancer growth and differentiation.

OBJECTIVES: Gastric cancer is etiologically related to interactions between Helicobacter pylori (H. pylori) infection, environmental and host factors. Gastric carcinoma is associated with a cascade of increasing atrophic gastric mucosal damage. Prostate stem cell antigen (PSCA) polymorphisms have been associated with an increased risk of gastric cancer. We aimed to examine the interaction between PSCA polymorphisms and H. pylori in the progression of H. pylori-related gastritis.
METHODS: The genotypes (TT, TC and CC) of PSCA single nucleotide polymorphism rs2294008 among H. pylori infected and uninfected Bhutanese were compared with the severity of H. pylori-related gastritis [neutrophils, monocytes, atrophy scores, H. pylori density, and the presence and extent of intestinal metaplasia (IM)] using the updated Sydney system.
RESULTS: Biopsies from 339 participants were included. The proportion of biopsies with IM was significantly (P < 0.05) greater in those with the TT genotype than in either those with the CT or CC genotype. Although no significant differences were found in inflammation or H. pylori density scores, the scores for IM at both gastric corpus and antrum among participants infected by H. pylori with the TT genotype was significantly (P < 0.05) greater than in the C allele carriers.
CONCLUSION: PSCA TT genotype is associated with a more than a threefold increase in the prevalence and the extent of gastric mucosal IM compared to C allele carriers among H. pylori-infected Bhutanese.

Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility.

With the help of Fe3O4 nagnetic nanoparticles as a solid carrier and an excellent tool for separation, six SNP loci (rs2279115 of BCL2 gene, rs804270 of NEIL2 gene, rs909253 of LTA gene, rs2294008 of PSCA gene, rs3765524 and rs10509670 of PLCE1 gene) were selected to evaluate their relation to gastric cancer risk. Using two kinds of functionalized magnetic nanoparticles and universal tagged arrays, the whole operation procedure including genome DNA extraction and SNP genotyping was performed. All genotypes and allele frequencies were calculated in the cases and controls respectively to analyze their association with gastric cancer risk. Totally 200 pathological samples and 134 normal control subjects were collected. The results demonstrated that four SNP loci (rs2279115, rs804270, rs909253 and rs3765524) showed a potential association with gastric cancer risk, and the other two (rs2294008, rs10509670) possessed no difference/association among cases and controls.

Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial-mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow-up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC ≥5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene expression and CTC enumeration increased the concordance probability estimated value from 0.716 to 0.889 in comparison with CTC enumeration alone. For patients who received docetaxel plus prednisone as first-line chemotherapy, positive stem cell gene expression suggested a poor PSA-PFS (p = 0.01) and a low PSA response rate (p = 0.008). However, CTC enumeration and EMT gene expression status did not affect PSA-PFS or PSA response rates. As a result, detection of peripheral blood stem cell gene expression could complement CTC enumeration in predicting OS and docetaxel-based treatment effects in mCRPC patients.

BACKGROUND AND OBJECTIVES: Prostate stem cell antigen (PSCA) is a cell surface, glycosylphosphatidylinositol (GPI)-anchored glycoprotein. Its overexpression has been detected in both local and metastatic prostate cancer (PCa), making it a potential therapeutic target. We previously reported that silencing PSCA by small interfering RNA targeting human PSCA (siRNA-PSCA) inhibited biological activity of PSCA-positive PCa cells leading to reduced proliferation, motility and invasion in vitro. In this study, we extended this in vitro findings to in vivo settings in order to investigate the effects of this specific siRNA on the tumor growth and metastasis development of PCa in vivo.
MATERIALS AND METHODS: The siRNA-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa PC-3M and LNCaP cells, respectively, and were subcutaneously inoculated into the male SCID mice. Tumor growth was measured with a caliper, and formation of metastasis in mice bearing xenograft tumors was studied by magnetic resonance imaging (MRI) and autopsy analysis. Western blot and immunohistochemistry were used to assess the expression levels of PSCA protein in tumor tissues from xenograft and distant metastases.
RESULTS: Consistent with our previous in vitro findings, the subcutaneous xenografts of PC-3M-siPSCA exhibited the almost completely inhibited expression of PSCA protein in their tumors tissues (P < 0.001 and P < 0.001, respectively), and consequently had a significant reduction in tumor growth volumes (P < 0.05 for all), and metastasis onset and sites (P < 0.001 for all) compared to those of PC-3M and PC-3M-siScrm. Conversely, LNCaP-PSCA showed significantly enhanced primary tumor growth and metastasis formation of xenografts compared to LNCaP-vehicle and LNCaP cells (P < 0.001 for all). Moreover, the up-regulated expression of PSCA protein was detected in the distant metastases of xenograft tumors from all groups.
CONCLUSIONS: Taken together, these observations suggest that PSCA has a promoting role in the growth and metastasis of PCa and siRNA-PSCA may be a potential therapeutic strategy for PSCA-positive PCa.

BACKGROUND: Polymorphisms of genes encoding PSCA, PLCE1 and MUC1 have been associated with the risk of different cancers in genome wide association studies (GWAS). Up to date there are limited data on the role of these genetic alterations in colorectal cancer (CRC) development. The aim of this study was to evaluate potential associations between single nucleotide polymorphisms (SNPs) of genes encoding PSCA, PLCE1 and MUC1 and the presence of CRC in European populations.
MATERIALS AND METHODS: Gene polymorphisms were analyzed in 574 European subjects (controls: n=382; CRC: n=192). PSCA C>T (rs2294008), PSCA G>A (rs2976392), MUC1 A>G (rs4072037) and PLCE1 A>G (rs2274223) SNPs were genotyped by RT-PCR.
RESULTS: The distribution of genotypes for all four SNPs was in line with the Hardy-Weinberg equilibrium (rs2294008, P=0.153; rs2976392, P=0.269; rs4072037, P=0.609; rs2274223, P=0.858). The distribution of genotypes and alleles of PSCA C>T, PSCA G>A, MUC1 A>G and PLCE1 A>G SNPs was similar among controls and CRC patient groups (P>0.05). GG genotype of MUC1 SNP was more frequent in CRC patients (24.0%) than in controls (20.2%); however, this association failed to reach significance (OR-1.45, P=0.15). Overall, in the present study SNPs of PSCA (rs2294008, rs2976392), MUC1 (rs4072037) and PLCE1 (rs2274223) genes were not associated with the presence of CRC.
CONCLUSIONS: Gene polymorphisms of PSCA, PLCE1 and MUC1 genes are not associated with the presence of CRC in European subjects.

BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Distant metastasis and local recurrence are still the major causes for failure of treatment in patients with nasopharyngeal carcinoma (NPC), making it urgent to further elicit the molecular mechanisms of NPC metastasis. Using a gene microarray including transcription factors and known markers for cancer stem cells, prostate stem cell antigen (PSCA) was found to be significantly down-regulated in metastatic NPC in lymph node, compared to its primary tumour, and in NPC cell lines with high metastatic ability compared to those with low metastatic ability. NPC patients with low PSCA expression had a consistently poor metastasis-free survival (p = 0.003). Knockdown and overexpression of PSCA respectively enhanced and impaired the migration and invasion in vitro and the lung metastasis in vivo of NPC cells. Mechanistically, the enhancement of NPC metastasis by knocking down PSCA probably involved epithelial-mesenchymal transition (EMT), by up-regulating N-cadherin and ZEB1/2 and by activating RhoA. The down-regulation of PSCA in NPC cells resulted directly from the binding of Slug to the PSCA promoter. PSCA may be a potential diagnostic marker and therapeutic target for patients with NPC.

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

The ly-6 proteins are a large family of proteins that resemble the snake three finger alpha toxins such as α-bungarotoxin and are defined by their multiple cysteine residues. Multiple members of the ly-6 protein family can modulate nicotinic signaling including lynx1, lynx2, slurp-1, slurp-2 and prostate stem cell antigen (PSCA). Consistent with the expression of multiple nicotinic receptors in bronchial epithelium, multiple members of the nicotinic-modulatory ly-6 proteins are expressed in lung including lynx1 and lynx2. We studied the role of lynx1 as an exemplar of the role of ly-6 proteins in lung. Our data demonstrates that lynx1 acts as a negative modulator of nicotinic signaling in normal and neoplastic lung. In normal lung lynx1 serves to limit the ability of chronic nicotine exposure to increase levels of nicotinic receptors and also serves to limit the ability of nicotine to upregulate levels of GABAA receptors in lung. In turn this allows lynx1 to limit the ability of nicotine to upregulate levels of mucin which is mediated by GABAergic signaling. This suggests that lynx1-mimetics may have potential for treatment of asthma and COPD. In that most lung cancer cells also express nicotinic receptor and lynx1 we examined the role of lynx-1 in lung cancer. Lynx1 levels are decreased in lung cancers compared to adjacent normal lung. Knockdown of lynx1 by siRNAs increased growth of lung cancer cells while expression of lynx1 in lung cancer cell decreased cell proliferation. This suggests that lynx1 is an endogenous regulator of lung cancer growth. Given that multiple small molecule negative and positive allosteric modulators of nicotinic receptors have already been developed, this suggests that lynx1 is a highly druggable target both for development of drugs that may limit lung cancer growth as well as for drugs that may be effective for asthma or COPD treatment.

Gastric adenocarcinoma (GAC) imposes a considerable health burden around the world. Gene variation in prostate stem cell antigen gene (PSCA) has been identified to be associated with GAC risk, while the results showed regional variation. To explore the influence of PSCA gene variation on its expression and GAC risk in the Northwest Chinese population, four single nucleotide polymorphisms (SNPs) of PSCA were genotyped in 476 GAC cases and 481 controls using MassARRAY system. Two SNPs of rs2294008 (C>T) and rs2976392 (G>A) were identified to be associated with GAC risk. rs2294008, rs2976392 and rs10216533 made up two statistically significant haplotypes (Hap-CGG and Hap-TAG). Additionally, PSCA expression was analyzed by quantitative real time PCR, immunohistochemistry and tissue microarray. The results showed that PSCA expression was decreased in GAC tissues compared with adjacent normal tissues. For normal tissues, PSCA expression was higher with Hap-TA than that with Hap-CG. For GAC tissues, the differentiation degree of Hap-TA was higher than that of Hap-CG. The expression distribution of PSCA in multiple human organs showed disparity. These results suggest that PSCA gene variation has a potential effect on its expression and GAC risk in the Northwest Chinese population.

BACKGROUND/AIM: In previous work, we found that prostate stem cell antigen (PSCA) gene, encoding a glycosylphosphatidylinositol-anchored protein, is a presumable tumor suppressor in gastric cancer and gallbladder cancer (GBC). The introduction of PSCA cDNA into GBC cell lines significantly suppressed tumorigenecity of cells in mice. The PSCA protein is thought to be involved in some form of intracellular signaling that remains to be elucidated.
MATERIALS AND METHODS: Using microarrays, we conducted gene-expression profiling on tumors generated by a GBC cell line TGBC-1TKB, with and without expression of PSCA, which was implanted into mice. Genes whose expression was down-regulated by PSCA were selected, and their down-regulation was confirmed by real-time PCR.
RESULTS: We identified several immune-related genes down-regulated by PSCA, including interleukin 8 (IL8), IL1 receptor antagonist (IL1RN) and S100 calcium-binding proteins A8 (S100A8) and A9 (S100A9).
CONCLUSION: PSCA signaling may suppress tumor growth in vivo by modulating immunological characteristics of GBC cells.

BACKGROUND: Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available.
METHODS: We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative).
RESULTS: Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110).
CONCLUSIONS: We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.