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Background: To explore the relationship between family history of esophageal cancer, SNPs, and the risk of esophageal squamous cell carcinoma (ESCC), we performed a population-based case-control study and developed a genetic family history-related risk (GFR) score and non-family history-related risk (GnFR) score to quantify the cumulative number of risk genotypes carried by each individual., Methods: We used data of 700 patients with nonfamilial ESCC, 341 patients with familial ESCC, 1,445 controls without a family history of esophageal cancer, and 319 controls with a family history. We genotyped 87 genetic variants associated with the risk for ESCC, and constructed GFR and GnFR scores for cases and controls., Results: Our results show that ESCC risk increased with higher GFR score ( P trend = 0.0096). Among the familial subgroup, we observed a nearly 7-fold [95% confidence interval (CI), 1.92-24.77] higher risk of ESCC in the highest GFR score group. The corresponding estimate was only 2-fold (95% CI, 1.41-3.93) higher risk of ESCC, in the stratum without a reported family history of esophageal cancer. Certain cell signaling pathways and immune-related pathways were enriched, specifically in familial ESCC. Results from a reconstructed cohort analysis demonstrated that cumulative risk to get esophageal cancer by age 75 years was 13.3%, 10.2%, 8.2%, and 5.1%, respectively, in four subgroups as defined by first-degree relatives of cases or controls with high or low genetic risk score. In particular, the cohort of relatives of ESCC cases with low genetic risk score exhibit a higher cumulative risk than the cohort of relatives of controls with high genetic risk score. It demonstrates that environmental factors play a major role in esophageal cancer., Conclusions: Further studies are warranted to dissect the mechanisms of shared environmental and genetic susceptibility affecting the risk of getting ESCC., Impact: Our study highlights that the need of preventive strategies to screen certain genetic polymorphisms, especially in individuals whose relatives had ESCC., (©2019 American Association for Cancer Research.)

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.

Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42-0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43-0.94) and non-drinkers (OR = 0.79, 95% CI = 0.64-0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37-0.83) and non-drinker (adjusted OR = 0.75, 95% CI = 0.60-0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene-gene interactions among three AKT1 SNPs (P < 0.015). A three-AKT1 SNP haplotype (C-A-C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52-0.94). Multifactor dimensionality reduction analysis confirmed a high-order gene-environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene-environment interplay in ESCC carcinogenesis., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

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.

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.

Introduction: Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that functions as a key regulator of gene transcription, protein translation, and autophagy. No studies have assessed associations between functional single nucleotide polymorphisms (SNPs) in mTORC1 genes and risk of esophageal squamous cell carcinoma (ESCC)., Methods: : In a case-control study of 1126 ESCC patients and 1131 cancer-free controls, we genotyped eight SNPs in mTORC1 (mTOR rs1883965 G>A and rs2536 T>C, mLST8 rs3160 C>T and rs26865 G>A, RPTOR rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A) and assessed their associations with risk of ESCC., Results: In the single-locus analyses, we found a significantly altered risk of ESCC associated with mTOR rs1883965 A variant genotypes (adjusted OR = 1.27 and 1.26; 95% confidence interval = 1.01-1.60 and 1.01-1.58 for GA and GA/AA, respectively, compared with GG) but not with other SNPs. In the combined analysis of the eight SNPs, we found individuals with two or more unfavorable genotypes exhibited an increased risk for ESCC (adjusted OR = 1.35; 95% confidence interval = 1.20-1.62), compared with those with less than two unfavorable genotypes. Such a cumulative effect was dose-dependent (ptrend = 0.004). In the multiple dimension reduction analysis, mTOR rs1883965 was consistently suggested as the strongest individual factor for ESCC risk, and the model including all SNPs yielded the lowest prediction error of 17.66% for model validation., Conclusions: These findings suggest that functional SNPs of mTORC1 genes may individually or collectively contribute to ESCC risk. Further validation of these findings is warranted.

Objective: To assess the association between single nucleotide polymorphisms (SNPs) of mannose-binding lectin 2 gene (MBL2) (rs1800450, rs1800451 and rs11003125) and protein kinase C-beta 1 gene (PRKC beta 1) (rs3700106, rs2575390) with diabetic macroangiopathy in northern Chinese Han population., Methods: The samples have included 318 type 2 diabetes mellitus (T2DM) patients and 448 normoglycemic controls. The five SNPs were determined by a Multiplex SnaPshot method. Biochemical indices such as fasting plasma-glucose, triglyceride and total cholesterol were also measured. Linkage disequilibrium and haplotype analysis were carried out for all samples using Haploview 4.2. Additive model was applied to assess the effect of interaction between SNPs and environment factors on macrovascular complications., Results: Genotypic frequencies of rs11003125 have differed significantly between the controls and patients with coronary heart disease and peripheral vascular disease (P=0.024 and 0.004, respectively). The allele frequency of rs11003125 was also statistically significant between the two groups (P=0.014 and 0.001, respectively). Compared with patients without macrovascular complications, the allele frequency of rs11003125 was significantly different in patients with peripheral vascular disease (P=0.031). No significant differences were found between the distribution of the genotype frequency and allele frequencies of other variants. Haplotype analysis indicated that, compared with controls and patients without macrovascular complications, individuals with G allele of rs1800450 and C allele of rs11003125 had a higher risk for macrovascular complications., Conclusion: The rs11003125 polymorphism located in the promoter region of MBL2 gene is associated with macrovascular complications of T2DM in northern Chinese Han population. G allele of rs1800450 and C allele of rs11003125 may be risk factors for macrovascular complications. There were additive interactive effects for rs11003125 polymorphism (GC+CC) and hypertension, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy on macrovascular complications.

Background: Non-Hodgkin's lymphoma (NHL) has been reported to be associated with autoimmune and pro-inflammatory response, and genetic polymorphisms of candidate genes involved in autoimmune and pro-inflammatory response may influence the susceptibility to NHL. To evaluate the role of such genetic variations in risk of NHL, we conducted a case-control study of 514 NHL patients and 557 cancer-free controls in a Chinese population., Method: We used the Taqman assay to genotype six potentially functional single nucleotide polymorphisms (SNPs) in six previously reported inflammation and immune-related genes (TNF rs1799964T>C, LTA rs1800683G>A, IL-10 rs1800872T>G, LEP rs2167270G>A, LEPR rs1327118C>G, TNFAIP8 rs1045241C>T). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI)., Results: We observed a significantly increased risk of NHL associated with the TNFAIP8 rs1045241C>T polymorphism (adjusted OR = 3.03; 95% CI = 1.68-5.45 for TT vs. CC and adjusted OR = 2.03; 95% CI = 1.53-2.69 for CT/TT vs. CC). The risk associated with the T allele was more evident in subgroups of 40-60 year-old, non-smokers or light-smokers (less than 25 pack-years), and subjects with normal weight or overweight. Risk for both B and T cell non-Hodgkin's lymphoma was elevated for CT/TT genotypes (adjusted OR = 1.95, 95% CI = 1.41-2.70 for B cell NHL and adjusted OR = 2.22, 95% CI = 1.49-3.30 for T cell NHL), particularly for DLBCL (adjusted OR = 2.01, 95%CI = 1.41-2.85) and FL (adjusted OR = 2.53, 95% CI = 1.17-5.45). These risks were not observed for variant genotypes of other five SNPs compared with their common homozygous genotypes., Conclusions: The polymorphism of TNFAIP8 rs1045241C>T may contribute to NHL susceptibility in a Chinese population. Further large-scale and well-designed studies are needed to confirm these results.

Background: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk., Methodology/principal Findings: In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR = 0.76, 95% CI = 0.63-0.93, CT/CC: adjusted OR = 0.80, 95% CI = 0.67-0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis., Conclusions/significances: These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.

To investigate the association between chromosome 8p11 (CHRNB3-CHRNA6) polymorphisms and lung cancer susceptibility in Chinese Han population, we genotyped 6 tag SNPs variants of this region among 784 patients with lung cancer and 782 age- and sex-matched cancer-free control participants to screen for any risk-associated SNPs. The results revealed that rs16891561 TT genotype had a protective effect against lung cancer in people over 60 years old (adjusted OR=0.42, 95% CI=0.20-0.88; P=0.022), female groups (adjusted OR=0.34, 95% CI=0.13-0.87; P=0.025), and non-smoking people (adjusted OR=0.32, 95% CI=0.13-079; P=0.013). Additionally, rs4236926 TT genotype had a protective effect against lung cancer in people over 60 years old (adjusted OR=0.48, 95% CI=0.23-0.99; P=0.048) and non-smoking people (adjusted OR=0.32, 95% CI=0.13-0.80; P=0.014). According to pathological type of lung cancer, these two SNPs were associated with adenocarcinomas susceptibility. As to cumulative effect of rs4236926 and rs16891561, in non-smokers strata, lung cancer risk was significantly reduced in those who had 3-4 mutant alleles (adjusted OR=0.29, 95% CI=0.11-0.71; P=0.007). Furthermore, people containing 3-4 mutant alleles had lower level of smoking doses (mean pack-year=13.2) compared with others. In conclusion, 8p11 (CHRNB3-CHRNA6) polymorphisms are related to smoking behavior and lung cancer susceptibility in Chinese Han population.