Association of THBS1 rs1478605 T>C in 5'-untranslated regions with the development and progression of gastric cancer.
ABSTRACT: Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single-nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the THBS1 gene on the development and progression of gastric cancer. In the case-control study, 275 gastric cancer patients and 275 cancer-free controls were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism. The data demonstrated that THBS1 rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39-0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23-0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14-0.52; P<0.001). The THBS1 CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33-0.93; P=0.02). By contrast, no association was observed between THBS1 rs3743125 and the development and progression of gastric cancer. These results suggest that THBS1 rs1478605 represents a potential molecular marker for gastric cancer.
Project description:MiR-124 functions as a tumor suppressor and plays an important role in tumorigenesis. A common polymorphism (rs531564, C>G) in the pri-miR-124 has been recently studied in connection with cancer risk. The aim of the present study was to investigate the association between pri-miR-124 rs531564 polymorphism and the risk and clinicopathological characteristics of colorectal cancer (CRC). Two case-control studies involving 900 CRC patients and 1110 cancer-free controls showed that pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of CRC in Xuzhou population [GG vs. CC: OR = 0.25, 95%CI = 0.09-0.67, P = 0.003; (CG+GG) vs. CC: OR = 0.73, 95%CI = 0.56-0.94, P = 0.01; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.10-0.70, P = 0.004; G vs. C: OR = 0.70, 95%CI = 0.56-0.89, P = 0.003], Bengbu population [GG vs. CC: OR = 0.20, 95%CI = 0.04-0.90, P = 0.02; GG vs. (CC+CG): OR = 0.21, 95%CI = 0.05-0.95, P = 0.03; G vs. C: OR = 0.72, 95%CI = 0.54-0.98, P = 0.03] and pooled population [GG vs. CC: OR = 0.26, 95%CI = 0.11-0.59, P<0.001; (CG+GG) vs. CC: OR = 0.76, 95%CI = 0.62-0.93, P = 0.008; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.12-0.62, P < 0.001; G vs. C: OR = 0.71, 95%CI = 0.59-0.85, P<0.001]. Additionally, pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of poor differentiation and lymph node metastasis of CRC. Our results suggest that pri-miR-124 rs531564 polymorphism may be a genetic modifier for developing CRC. However, further studies are needed to validate our findings.
Project description:Previous studies have identified the prostate stem cell antigen (PSCA) gene rs2294008 C > T and rs2976392 G > A polymorphisms to be associated with the risk of gastric cancer, the results of which are inconsistent. The present study aimed to evaluate the association between the two polymorphisms and the gastric cancer risk in the Chinese population. A hospital-based case-control study was conducted on 549 cases and 592 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the association of the two polymorphisms on the gastric cancer risk. We found that both rs2294008 (CT vs. CC, OR = 1.55, 95% CI = 1.20-1.99, P<0.001 and CT+TT vs. CC, OR = 1.38, 95% CI = 1.09-1.74, P=0.008) and rs2976392 (GA vs. GG, OR = 1.61, 95% CI = 1.25-2.07, P<0.001 and GA+AA vs. GG, OR = 1.52, 95% CI = 1.20-1.92, P<0.001) were associated with an increased gastric cancer. In the combined analysis of the two polymorphisms, subjects with more than one risk genotype have a significantly increased risk of gastric cancer (OR = 1.38, 95% CI = 1.09-1.75, P=0.008) in comparison with those without any risk genotypes. In conclusion, our findings verified that the PSCA gene rs2294008 and rs2976392 polymorphisms were both significantly associated with an increased risk of gastric cancer in the Chinese population. Well-designed functional studies are to be warranted to confirm these findings.
Project description:The role of an extracellular matrix- (ECM-) receptor interaction signature has not been fully clarified in gastric cancer. This study performed comprehensive analyses on the differentially expressed ECM-related genes, clinicopathologic features, and prognostic application in gastric cancer. The differentially expressed genes between tumorous and matched normal tissues in The Cancer Genome Atlas (TCGA) and validation cohorts were identified by a paired t-test. Consensus clusters were built to find the correlation between clinicopathologic features and subclusters. Then, the least absolute shrinkage and selection operator (lasso) method was used to construct a risk score model. Correlation analyses were made to reveal the relation between risk score-stratified subgroups and clinicopathologic features or significant signatures. In TCGA (26 pairs) and validation cohort (134 pairs), 25 ECM-related genes were significantly highly expressed and 11 genes were downexpressed in gastric cancer. ECM-based subclusters were slightly related to clinicopathologic features. We constructed a risk score model = 0.081?log2?(CD36) + 0.043?log2?(COL5A2) + 0.001?log2?(ITGB5) + 0.039?log2?(SDC2) + 0.135?log2?(SV2B) + 0.012?log2?(THBS1) + 0.068?log2?(VTN) + 0.023?log2?(VWF). The risk score model could well predict the outcome of patients with gastric cancer in both training (n = 351, HR: 1.807, 95% CI: 1.292-2.528, P = 0.00046) and validation (n = 300, HR: 1.866, 95% CI: 1.347-2.584, P = 0.00014) cohorts. Besides, risk score-based subgroups were associated with angiogenesis, cell adhesion molecules, complement and coagulation cascades, TGF-beta signaling, and mismatch repair-relevant signatures (P < 0.0001). By univariate (1.845, 95% CI: 1.382-2.462, P < 0.001) and multivariate (1.756, 95% CI: 1.284-2.402, P < 0.001) analyses, we regarded the risk score as an independent risk factor in gastric cancer. Our findings revealed that ECM compositions became accomplices in the tumorigenesis, progression, and poor survival of gastric cancer.
Project description:To determine the association of single nucleotide polymorphisms (SNPs) of the thrombospondin 1 (THBS1) gene with development of chronic ocular surface inflammation (keratoconjunctivitis) after refractive surgery.Retrospective cohort study.Active duty U.S. Army soldiers (n = 143) who opted for refractive surgery.Conjunctival impression cytology samples collected from participants before the surgery were used to harvest DNA for genotyping 5 THBS1 SNPs (rs1478604, rs2228262, rs2292305, rs2228262, and rs3743125) using the Sequenom iPLEX Gold platform (Sequenom, San Diego, CA). Samples collected after surgery were used to harvest RNA for gene expression analysis by real-time polymerase chain reaction (PCR). Participants were followed for 1 year after surgery to monitor the status of keratoconjunctivitis.Genetic basis of the development of chronic keratoconjunctivitis after refractive surgery.Carriers of minor alleles of 3 SNPs each were found to be more susceptible to developing chronic keratoconjunctivitis (rs1478604: odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41-4.47; P = 2.5 × 10(-3); rs2228262 and rs2292305: OR, 1.9; 95% CI, 1.05-3.51; P = 4.8 × 10(-2)). Carriers of the rs1478604 minor allele expressed significantly reduced levels of thrombospondin 1 (TSP1) (P = 0.042) and increased levels of an inflammatory cytokine associated with keratoconjunctivitis, interleukin-1? (P = 0.025), in their ocular surface epithelial cells compared with homozygous major allele controls.Genetic variation in the THBS1 gene that results in decreased expression of the encoded glycoprotein TSP1 in ocular surface epithelial cells significantly increases the susceptibility to develop chronic ocular surface inflammation after refractive surgery. Further investigation of THBS1 SNPs in a larger sample size is warranted.
Project description:The transforming growth factor-β (TGFβ) pathway plays an important role in various types of human cancer. However, the role of TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms in gastric cancer is controversial. We aimed to investigate the associations between these polymorphisms and gastric cancer susceptibility, clinicopathological parameters and survival. A case-control study was conducted in 1,010 gastric cancer patients and 1,500 healthy controls. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. Compared with the TT genotype, the TGFB1 -509 C allele (CT/CC) was significantly associated with a reduced risk of gastric cancer (OR, 0.71; 95% CI, 0.58-0.87; p=0.001) and certain subtypes of gastric cancer including intestinal type (OR, 0.70; 95% CI, 0.57-0.87; p=0.001), poorly differentiated (OR, 0.67; 95% CI, 0.54-0.85; p=0.001) and stage TNM III+IV (OR, 0.73; 95% CI, 0.58-0.92; p=0.008). Compared with the TGFBR2 -875 GG genotype, carriers of the A allele (AA/AG) had a significantly decreased gastric cancer risk (OR, 0.58; 95% CI, 0.62-0.91; P<0.001). A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles was associated with a further decreased risk of gastric cancer (OR, 0.42; 95% CI, 0.32-0.57, p<0.001). No significant correlation was observed between polymorphisms and survival of gastric cancer patients. Our results suggest that both the TGFB1 -509 and TGFBR2 -875 polymorphisms contribute to a decreased gastric cancer risk. The TGFB1 -509 polymorphism affects certain subtypes of gastric cancer according to clinicopathological parameters. A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles conferred a further decreased gastric cancer risk. These findings provide clues to the biological mechanisms that underline tumor heterogeneity.
Project description:Because to date there is no available study on STAT3 polymorphism and gastric cancer in Western populations and taking into account that Helicobacter pylori CagA EPIYA-C segment deregulates SHP-2/ERK-JAK/STAT3 pathways, we evaluated whether the two variables are independently associated with gastric cancer.We included 1048 subjects: H. pylori-positive patients with gastric carcinoma (n = 232) and with gastritis (n = 275) and 541 blood donors. Data were analyzed using logistic regression model.The rs744166 polymorphic G allele (p = 0.01; OR = 1.76; 95 % CI = 1.44-2.70), and CagA-positive (OR = 12.80; 95 % CI = 5.58-19.86) status were independently associated with gastric cancer in comparison with blood donors. The rs744166 polymorphism (p = 0.001; OR = 1.64; 95 % CI = 1.16-2.31) and infection with H. pylori CagA-positive strains possessing higher number of EPIYA-C segments (p = 0.001; OR = 2.28; 95 % CI = 1.41-3.68) were independently associated with gastric cancer in comparison with gastritis. The association was stronger when host and bacterium genotypes were combined (p < 0.001; OR = 3.01; 95 % CI = 2.29-3.98). When stimulated with LPS (lipopolysaccharide) or Pam3Cys, peripheral mononuclear cells of healthy carriers of the rs744166 GG and AG genotypes expressed higher levels of STAT3 mRNA than those carrying AA genotype (p = 0.04 for both). The nuclear expression of phosphorylated p-STAT3 protein was significantly higher in the antral gastric tissue of carriers of rs744166 GG genotype than in carriers of AG and AA genotypes.Our study provides evidence that STAT3 rs744166 G allele and infection with CagA-positive H. pylori with higher number of EPIYA-C segments are independent risk factors for gastric cancer. The odds ratio of having gastric cancer was greater when bacterium and host high risk genotypes were combined.
Project description:Objectives In the present study, we examined available articles from online databases to comprehensively investigate the effect of the XPC (xeroderma pigmentosum complementation group C) rs2228000 polymorphism on the risk of different types of clinical cancer. Methods We conducted a group of overall and subgroup pooling analyses after retrieving the data from four databases (updated till September 2019). The P-value of association, OR (odds ratios), and 95% CI (confidence interval) were calculated. Results We selected a total of 71 eligible studies with 26835 cancer cases and 37069 controls from the 1186 retrieved articles. There is an enhanced susceptibility for bladder cancer cases under T vs. C [P=0.004; OR (95% CI) = 1.25 (1.07, 1.45)], TT vs. CC [P=0.001; 1.68 (1.25, 2.26)], CT+TT vs. CC [P=0.016; 1.26 (1.04, 1.53)], and TT vs. CC+ CT [P=0.001; 1.49 (1.18, 1.90)] compared with negative controls. Additionally, there is an increased risk of breast cancer under T vs. C, TT vs. CC and TT vs. CC+ CT (P<0.05, OR > 1). Nevertheless, there is a decreased risk of gastric cancer cases in China under T vs. C [P=0.020; 0.92 (0.85, 0.99)], CT vs. CC [P=0.001, 0.83 (0.73, 0.93)], and CT+TT vs. CC [P=0.003, 0.84 (0.76, 0.94)]. Conclusions The TT genotype of XPC rs2228000 may be linked to an increased risk of bladder and breast cancer, whereas the CT genotype is likely to be associated with reduced susceptibility to gastric cancer in the Chinese population.
Project description:Gastric cancer (GC) is the fifth most common cancer and imposes a global cancer burden. IL-4 is a typical cytokine of Th2 cells. IL-4 genetic polymorphisms have multiple functions in many cancers. We performed a case-control study in the Chinese population, and evaluated the association between rs2243250 (590 C/T), rs2227284 (107 T/C), rs2070874 (166 T/C) and rs1801275 (576 Q/R) and gastric cancer risk. A total of 340 gastric cancer patients and 364 controls were enrolled into our study. SNP genotyping of IL-4 rs2243250, rs2227284, rs2070874 and rs1801275 was done in a 384-well plate format on the sequenom MassARRAY platform (Sequenom, San Diego, USA). We observed the CC genotype of IL-4 rs2243250 was associated with risk of gastric cancer when compared with the TT genotype (OR=2.36, 95% CI=1.49-3.75). Moreover, individuals harboring the CT+CC genotype exposed a higher risk of gastric cancer in comparison with the TT genotype (OR=1.66, 95% CI=1.17-2.35). However, there was no significant association between IL-4 rs2227284, rs2070874 and rs1801275 and gastric cancer risk. The TT+CT genotype of IL-4 rs2243250 showed a significant increased risk of gastric cancer in males (OR=2.48, 95% CI=1.67-3.68) and those without a family history of cancer (OR=1.97, 95% CI=1.44-2.70). In ever drinkers (OR=2.04, 95% CI=1.24-3.37) and H. pylori infected patients (OR=2.31, 95% CI=1.38-3.86), the TT+CT genotype of IL-4 rs2243250 had a higher risk of gastric cancer than non-drinkers (OR=1.77, 95% CI=1.20-2.61) and non-H. pylori infected ones (OR=1.76, 95% CI=1.19-2.62). The CTCA (OR=1.54, 95% CI=1.06-2.24), CTCG (OR=1.83, 95% CI=1.16-2.86) and CTTG (OR=1.89, 95% CI=1.16-3.07) haplotypes showed an increased risk in gastric cancer, while the TCTG (OR=0.22, 95% CI=0.09-0.52), TTCG (OR=0.47, 95% CI=0.32-0.69) and TTTA (OR=0.58, 95% CI=0.42-30.79) haplotypes were associated with an reduction risk of gastric cancer. In conclusion, our study indicated that the IL-4 rs2243250 CC genotype and CT+CC genotype were associated with gastric cancer risk in the Chinese population, and IL-4 haplotypes plays an important role in the development of gastric cancer.
Project description:<h4>Purpose</h4>Numerous studies have suggested that the interleukin-4 (IL-4) rs2243250 polymorphism is associated with gastric cancer susceptibility. However, the results were inconsistent. Hence, we carried out a meta-analysis to confirm the conclusion.<h4>Methods</h4>We searched PubMed, Embase, CBM, CNKI, and Wanfang Data to identify relevant studies up to August 20, 2015. Odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association between IL-4 rs2243250 polymorphism and gastric cancer susceptibility. All the statistical analyses were performed with Stata 12.0 software.<h4>Results</h4>A total of eleven published case-control studies were identified, including 2,247 gastric cancer patients and 3,370 controls. Overall, no significant association between IL-4 rs2243250 polymorphism and gastric cancer susceptibility was observed in this meta-analysis (T vs C: OR =1.05, 95% CI =0.95-1.17; TT vs CC: OR =1.20, 95% CI =0.89-1.63; CT vs CC: OR =1.14, 95% CI =0.87-1.48; TT + CT vs CC: OR =1.13, 95% CI =0.89-1.44; TT vs CT + CC: OR =1.02, 95% CI =0.88-1.20). Similar results were found in subgroup analyses according to ethnicity and Hardy-Weinberg equilibrium in controls.<h4>Conclusion</h4>This meta-analysis suggests that IL-4 rs2243250 polymorphism may not be associated with gastric cancer susceptibility. Further studies are needed to validate this conclusion.
Project description:Background:Helicobacter pylori (H. pylori)-induced gastric cancer is an intricate progression of immune response against H. pylori infection. IL-16, TGF-?1 and TLR4 pathways were the mediators involved in the immune response. We hypothesized that genetic variations in genes of these pathways have potential susceptibility to gastric cancer risk, and predict clinical outcomes of patients. Methods:To investigate the susceptibility and prognostic value of genetic variations of IL-16, TGFBR1 and TLR4 pathways to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. Genotyping for all polymorphisms was based on the Sequenom's MassARRAY platform, and H. pylori infection was determined by using an immunogold testing kit. Results:We found rs10512263 CC genotype was found to be a decreased risk of gastric cancer (CC vs. TT: adjusted OR?=?0.54, 95% CI 0.31-0.97); however, rs334348 GG genotype was associated with increased risk of gastric cancer (GG vs. AA: adjusted OR?=?1.51, 95% CI 1.05-2.18). We found that carriers harboring rs1927911 A allele (GA/AA) or rs10512263 C allele (CT/CC) have unfavorable survival time than none carriers (rs1927911: GA/AA vs. GG: adjusted HR?=?1.27, 95% CI 1.00-1.63; rs10512263: CT/CC vs. TT: adjusted HR?=?1.29, 95% CI 1.02-1.63) and that individuals harboring both two minor alleles (rs1927911 GA/AA and rs10512263 CT/CC) suffered a significant unfavorable survival (adjusted HR?=?1.64, 95% CI 1.17-2.31). Conclusion:In short, we concluded that two polymorphisms (rs334348, rs10512263) in TGFBR1 were associated with risk of gastric cancer, and that TLR4 rs1927911 and TGFBR1 rs10512263 were associated with clinical outcomes of gastric cancer patients.