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MDM4 is a p53-interacting protein and plays an important role in carcinogenesis. In this study of 1,077 gastric cancer (GCa) cases and 1,173 matched cancer-free controls, we investigated associations between three tagging single nucleotide polymorphisms (SNPs) (rs11801299 G>A, rs1380576 C>G and rs10900598 G>T) in MDM4 and gastric cancer risk in an Eastern Chinese Population. In logistic regression analysis, a significantly decreased GCa risk was associated with the rs1380576 GG variant genotype (adjusted odds ratio [OR] =0.74, 95% confidence interval [CI] =0.56-0.98) under a recessive model, which remained significant after correction by the false-positive reporting probability. This risk was more evident in subgroups of older subjects, males, never smokers, never drinkers and cancers of non-cardia. We then performed SNP-mRNA expression correlation analysis and found that the GG variant genotype was associated with significantly decreased expression of MDM4 mRNA in normal cell lines for 44 Chinese (P=0.032 for GG vs. CC) as well as for 269 multi-ethnic subjects (P<0.0001 for GG vs. CC). Our results suggest that the MDM4 rs1380576 G variant may be markers for GCa susceptibility. Larger, independent studies are warranted to validate our findings.

Interleukin-17 plays a crucial role in inflammation-related carcinogenesis. We hypothesize that genetic variants in IL-17 are associated with gastric cancer (GCa) risk, and we genotyped five potentially functional single nucleotide polymorphisms (SNPs) (rs1974226 G > A, rs2275913 A > G, rs3819024 A > G, rs4711998 A > G, and rs8193036 C > T) of IL-17 in 1121 GCa patients and 1216 cancer-free controls in an eastern Chinese population. Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Meta-analysis and genotype-mRNA expression correlation were performed to further validate positive associations. We found that an increased GCa risk was independently associated with rs1974226 (adjusted OR = 2.60, 95% CI = 1.27-5.32 for AA vs. GG + GA) and rs2275913 (adjusted OR = 1.33, 95% CI = 1.03-1.72 for GA + AA vs. GG), while a decreased GCa risk was independently associated with rs3819024 (adjusted OR = 0.72, 95% CI = 0.54-0.96 for GG vs. AA + AG). Additional meta-analyses confirmed the observed risk association with rs2275913. We also found that two IL-17 haplotypes (G-G-G-A-C) and (A-G-G-A-C) (in the order of rs1974226, rs2275913, rs3819024, rs4711998 and rs8193036) were associated with a reduced GCa risk (adjusted OR = 0.64, 95% CI = 0.46-0.89 and adjusted OR = 0.38, 95% CI = 0.17-0.81, respectively). However, the expression Quantitative Trait Locus (eQTL) analysis for the genotype-phenotype correlation did not find mRNA expression changes associated with either the genotypes. In conclusions, genetic variants of IL-17 are likely to be associated with risk of GCa, and additional larger studies with functional validation are needed to explore the molecular mechanisms underlying the observed associations.

The single nucleotide polymorphism (SNP) rs2910164 G>C within miR-146a has been reported that is associated with the increased risk of gastric cancer (GCa). However, the results are inconclusive, espicially among Asian populations, which probably due to small sample size in each single study. To validate this association and get a more precise estimation, we conducted a large GCa study including 1,125 cases and 1,196 controls in an eastern Chinese population. Our results showed that this SNP was not associated with GCa risk in either of the three genetic models [co-dominant model: CG vs. CC, odds ratio (OR) = 0.99, 95% confidence interval (95%CI): 0.83-1.19; GG vs. CC, OR = 1.03, 95%CI: 0.81-1.32; dominant model: (CG+GG) vs. CC, OR = 1.00, 95%CI = 0.84-1.19; recessive model: GG vs. (CG+CC), OR = 1.04, 95%CI = 0.83-1.29]. Stratified analysis by age, gender, smoking status, drinking status, or tumor location confirmed this non-significant association. In summary, these results suggest that the miR-146a SNP rs2910164 may not be a risk factor for GCa in this Chinese population. Larger and well-designed, preferably prospective studies are needed to further confirm our findings., Competing Interests: The authors have declared that no competing interests exist.

The interleukin-6 (IL-6)/JAK/STAT3 signaling pathway plays a central role in inflammation-mediated cancers, including gastric cancer (GCa). We evaluated associations between 10 potentially functional single nucleotide polymorphisms (SNPs) of four essential genes in the pathway and GCa risk in a study of 1,125 GCa cases and 1,221 cancer-free controls. We found that a significant higher GCa risk was associated with IL-6 rs2069837G variant genotypes [adjusted odds ratios (OR) = 1.33; 95% confidence interval (CI) = 1.12-1.59 for AG + GG vs. AA)] and JAK1 rs2230587A variant genotypes (adjusted OR = 1.20; 95% CI = 1.02-1.43 for GA + AA vs. GG). We also found that a significant decreased GCa risk was associated with STAT3 rs1053004G variant genotypes (adjusted OR = 0.84; 95% CI = 0.71-0.99 for AG + GG vs. AA). The combined analysis of IL-6 rs2069837G and JAK1 rs2230587A variant risk genotypes revealed that individuals with one-or-two risk genotypes exhibited an increased risk for GCa (adjusted OR = 1.34; 95% CI = 1.13-1.59). Genotypes and mRNA expression correlation analysis using the data from the HapMap 3 database provided further support for the observed risk associations. Larger studies are warranted to validate these findings., Competing Interests: The authors declare no conflict of interest.

Published data on the association between the MUC1 rs4072037A > G polymorphism and gastric cancer (GCa) risk were inconclusive. To derive a more precise estimation of the association, we conducted a large GCa study of 1,124 cases and 1,192 controls to confirm this association in an Eastern Chinese population. Our results showed that the G allele was strongly associated with a decreased GCa risk in the study population [GG vs. AA, odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.31-0.73; AG/GG vs. AA, OR = 0.82, 95% CI = 0.68-0.99; GG vs. AA/AG, OR = 0.48, 95% CI = 0.32-0.74]. These associations remained significant in subgroups of age, tumor site, drinking and smoking status. Moreover, this association was supported by an additional meta-analysis of published studies. In summary, these results suggest that the MUC1 rs4072037G allele may be a low-penetrating protection factor for GCa risk in Chinese populations.

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.

AKT is an important signal transduction protein that plays a crucial role in cancer development. Therefore, we evaluated associations between single nucleotide polymorphisms (SNPs) in the AKT promoter region and gastric cancer (GCa) risk in a case-control study of 1,110 GCa patients and 1,114 matched cancer-free controls. We genotyped five SNPs (AKT1 rs2494750G >C, AKT1 rs2494752A >G, AKT1 rs10138227C >T, AKT2 rs7254617G>A and AKT2 rs2304186G >T) located in the 5' upstream regulatory, first intron or promoter regions. In the logistic regression analysis, a significantly elevated GCa risk was associated with the rs2494752 AG/GG variant genotypes (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42) under a dominant genetic model, and this risk was more evident in subgroups of ever drinkers. The luciferase reporter assay showed that the rs2494752 G allele significantly increased luciferase activity. Our results suggest that the potentially functional AKT1 rs2494752 SNP may affect GCa susceptibility, likely by modulating the AKT1 promoter transcriptional activity. Larger, independent studies are warranted to validate our findings.

Published data on the association between PRKAA1 rs13361707 T > C polymorphism and gastric cancer (GCa) susceptibility were inconclusive. To derive a more precise estimation of the association, we conducted a large-scale GCa study of 1,124 cases and 1,194 controls to confirm this association in an eastern Chinese population. Our results showed that the C allele of PRKAA1 rs13361707 increased the GC risk in the study population [CT vs. TT, odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.40-2.12; CC vs. TT, OR = 2.15, 95%CI = 1.70-2.71; CT/CC vs. TT, OR = 1.86, 95%CI = 1.53-2.26; CC vs.TT/CT, OR = 1.49, 95%CI = 1.24-1.79]. In addition, the association of C allele with an increased GCa risk was still significant in subgroups, when stratified by age, sex, tumor site, drinking and smoking status. Moreover, the findings in the present study were validated by our further meta-analysis. In summary, these results indicated that the C allele of PRKAA1 rs13361707 was a low-penetrate risk factor for GCa.

Background and Aim: Genetic variants in the mammalian target of rapamycin (mTOR) gene have become an interesting topic for the study of genetic susceptibility to cancer, but their associations with the risk of gastric cancer have not been fully investigated., Materials and Methods: In a hospital-based case-control study of 1002 gastric cancer patients and 1003 cancer-free controls, we genotyped four potentially functional single nucleotide polymorphisms (SNPs) (rs1034528G>C, rs17036508T>C, rs3806317A>G, and rs2295080T>G) of mTOR and assessed their associations with the risk of gastric cancer using univariate and multivariate logistic regression analyses. We also used the multifactorial dimension reduction analysis to explore possible interactions and the false-positive report probabilities to assess significant findings., Results: We found that rs1034528 CG/CC and rs3806317 GA/GG variant genotypes were associated with an increased risk of gastric cancer under a dominant model (adjusted odds ratio=1.27 and 1.22, respectively). In the combined analysis of all four SNPs under investigation, patients with 3-4 risk genotypes of mTOR had a significantly increased risk of gastric cancer (adjusted odds ratio=1.46, 95% confidence interval=1.19-1.79) compared with those with 0-2 risk genotypes. Stratified analysis indicated that this risk was more pronounced in subgroups of men, never-smokers, never-drinkers, and clinical stages III+IV. The multifactorial dimension reduction analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer., Conclusion: These findings suggest that potentially functional SNPs of mTOR may individually or collectively contribute to the risk of gastric cancer. Larger studies with diverse ethnic populations are warranted to validate our findings.

Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions, and genetic variations in this complex may affect cancer risk. In this study, we examined the associations between eight potential functional single nucleotide polymorphisms in the mTORC1 genes (rs2536T>C and rs1883965G>A for mTOR, rs3160T>C, and rs26865A>G for mLST8, rs3751934C>A, rs1062935T>C, rs3751932T>C, and rs12602885G>A for Raptor, not included in published gastric cancer genome-wide association studies) and gastric cancer risk in 1125 gastric cancer cases and 1196 cancer-free controls. We performed conditional logistic regression and multifactor dimensionality reduction (MDR) analyses to assess their associations with gastric cancer risk. We also used false-positive report probabilities (FPRP) for assessing significant findings. We found that only the rs1883965A variant genotypes were associated with an increased risk of gastric cancer (AG vs. GG: adjusted odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.00-1.59; AA vs. GG: adjusted OR = 1.85, 95% CI = 0.67-5.16 and dominant model: adjusted OR = 1.28, 95% CI = 1.03-1.61). Patients with ≥1 risk genotypes of mTOR had significant increased risk (adjusted OR = 1.25, 95% CI = 1.04-1.49), compared with those having zero risk genotypes. In the stratified analysis, the risk effect of the rs1883965 AG/AA genotypes was evident in subgroups of ever-smokers, non-gastric cardia adenocarcinoma and clinical stage I + II, which were noteworthy findings as evaluated by FPRP. The MDR analysis identified smoking status and rs1883965 as the strongest two-factors for gastric cancer risk. These data support the hypothesis that functional polymorphisms of mTOR may contribute to gastric cancer risk. Clearly, our results require validation in larger studies with different ethnic populations., (© 2013 Wiley Periodicals, Inc.)

Background: Caspase 7 (CASP7) is an important regulator and executioner in the apoptosis pathway and plays a crucial role in cancer development and progression. However, few studies have evaluated associations between functional single nucleotide polymorphisms (SNPs) in the 3' untranslational region (UTR) of CASP7 and risk of gastric cancer., Methods: In a case-control study of 1117 patients with gastric cancer and 1146 cancer-free controls with frequency matching on age and sex, we genotyped four potentially functional SNPs (rs4353229T>C, rs10787498T>G, rs1127687G>A and rs12247479G>A) located in the microRNA binding sites of the CASP7 3' UTR by using Taqman assays and evaluated their associations with risk of gastric cancer by using logistic regression analyses as well as multifactorial dimension reduction (MDR) analysis., Results: In the single-locus analysis, only the CASP7 rs4353229 TT genotype was associated with 0.83-fold decreased risk (95% confidence interval [CI] = 0.70-0.98) of gastric cancer under a recessive model, compared with the CT/CC genotypes. In the combined analysis of all four SNPs, we found that the risk of gastric cancer decreased by 19% in those carrying any of the risk genotypes (adjusted odds ratio = 0.81, 95% CI = 0.68-0.96), compared with those carrying zero risk genotypes, and this risk was more evident in subgroups of younger age (<59 years), females, non-smokers, non-drinkers and patients with non-gastric cardia adenocarcinoma. Further MDR analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer., Conclusions: Potentially functional CASP7 variants may contribute to risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.

DNA repair genes play an important role in maintaining stability and integrity of genomic DNA. Polymorphisms in nucleotide excision repair genes may cause variations in DNA repair capacity phenotype and thus contribute to cancer risk. In this case-control study of 1,125 gastric cancer cases and 1,196 cancer-free controls, we investigated the association between three functional single nucleotide polymorphisms (SNPs, rs2296147T > C, rs2094258C > T and rs873601G > A) in the xeroderma pigmentosum group G (XPG) gene and gastric cancer risk. We used the Taqman assays to genotype these three SNPs and logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that only the rs873601A variant genotypes were associated with a significant higher risk for gastric adenocarcinoma (adjusted OR = 1.30, 95% CI = 1.03-1.64 for AA vs. GG and adjusted OR = 1.23, 95% CI = 1.01-1.49 for AA vs. GG/AG). Stratification analysis indicated that this risk was more pronounced in subgroups of older age (>59 years), males, ever-smokers, and patients with NGCA. All these were not found for the other two SNPs (rs2296147T > C and rs2094258C > T). We then performed expression analysis using gastric cancer adjacent normal tissues from 141 patients and found that the A variant allele was associated with non-significantly reduced expression of XPG mRNA (P(trend) = 0.107). Further analysis using mRNA expression data from the HapMap suggested that the A allele was associated with significantly reduced expression of XPG mRNA in normal cell lines for 45 Chinese (P(trend) = 0.003) as well as for 261 subjects with different ethnicities (P(trend) = 0.001). These support the hypothesis that functional XPG variants may contribute to the risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.

Background: Inherited functional single nucleotide polymorphisms (SNPs) in DNA repair genes may alter DNA repair capacity and thus contribute to cancer risk., Methods: Three ERCC1 functional SNPs (rs2298881C>A, rs3212986C>A and rs11615G>A) and two XPF/ERCC4 functional SNPs (rs2276466C>G and rs6498486A>C) were genotyped for 1125 gastric adenocarcinoma cases and 1196 cancer-free controls by Taqman assays. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate risk associations, and false-positive report probabilities (FPRP) were calculated for assessing significant findings., Results: ERCC1 rs2298881C and rs11615A variant genotypes were associated with increased gastric cancer risk (adjusted OR=1.33, 95% CI=1.05-1.67 for rs2298881 AC/CC and adjusted OR=1.23, 95% CI=1.05-1.46 for rs11615 AG/AA, compared with their common genotype AA and GG, respectively). Patients with 2-3 ERCC1 risk genotypes had significant increased risk (adjusted OR=1.56, 95% CI=1.27-1.93), compared with those with 0-1 ERCC1 risk genotypes, and this risk was more significantly in subgroups of never drinkers, non-gastric cardia adenocarcinoma (NGCA) and clinical stage I+II. All these risks were not observed for XPF SNPs., Conclusions: These findings suggest that functional ERCC1 SNPs may contribute to risk of gastric cancer. Larger and well-designed studies with different ethnic populations are needed to validate our findings.