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      PSCA rs2294008 C > T polymorphism contributes to gastric and bladder cancer risk.

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          Abstract

          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.

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          Association studies for finding cancer-susceptibility genetic variants.

          Cancer is the result of complex interactions between inherited and environmental factors. Known genes account for a small proportion of the heritability of cancer, and it is likely that many genes with modest effects are yet to be found. Genetic-association studies have been widely used in the search for such genes, but success has been limited so far. Increased knowledge of the function of genes and the architecture of human genetic variation combined with new genotyping technologies herald a new era of gene mapping by association.
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            Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer.

            Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.
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              Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer.

              The identification of cell surface antigens is critical to the development of new diagnostic and therapeutic modalities for the management of prostate cancer. Prostate stem cell antigen (PSCA) is a prostate-specific gene with 30% homology to stem cell antigen 2, a member of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA encodes a 123-aa protein with an amino-terminal signal sequence, a carboxyl-terminal GPI-anchoring sequence, and multiple N-glycosylation sites. PSCA mRNA expression is prostate-specific in normal male tissues and is highly up-regulated in both androgen-dependent and -independent prostate cancer xenografts. In situ mRNA analysis localizes PSCA expression in normal prostate to the basal cell epithelium, the putative stem cell compartment of the prostate. There is moderate to strong PSCA expression in 111 of 126 (88%) prostate cancer specimens examined by in situ analysis, including high-grade prostatic intraepithelial neoplasia and androgen-dependent and androgen-independent tumors. Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24.2, a region of allelic gain in more than 80% of prostate cancers. A mouse homologue with 70% amino acid identity and similar genomic organization to human PSCA has also been identified. These results support PSCA as a target for prostate cancer diagnosis and therapy.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and clinical risk management
                Informa UK Limited
                1176-6336
                1176-6336
                2015
                : 11
                Affiliations
                [1 ] Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
                [2 ] Department of Immunology and Pathogenic Biology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
                [3 ] Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
                [4 ] Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China ; Center for Translational Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
                Article
                tcrm-11-237
                10.2147/TCRM.S77089
                4335611
                25709466
                7860fd1f-27ba-48d8-87d3-8fe25adb64e7
                History

                SNPs,meta-analysis,prostate stem cell antigen,risk,single nucleotide polymorphisms

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