Meng Hong Sun

Genetic variations of mTORC1 genes and risk of gastric cancer in an eastern chinese population

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.

Polymorphisms in ERCC1 and XPF genes and risk of gastric cancer in an eastern Chinese population.

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.

A pri-miR-218 variant and risk of cervical carcinoma in Chinese women

BackgroundMicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma.MethodsIn this case–control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women.ResultsWe found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95, P=0.015). However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3. Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma.ConclusionsThe pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.

Tumor necrosis factor-α induced protein 8 polymorphism and risk of non-Hodgkin's lymphoma in a Chinese population: a case-control study.

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.

Polymorphisms in the ERCC5 Gene and Risk of Esophageal Squamous Cell Carcinoma (ESCC) in Eastern Chinese Populations

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.

Polymorphisms in mTORC1 Genes Modulate Risk of Esophageal Squamous Cell Carcinoma in Eastern Chinese Populations

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.

FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7

Cancer‐associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)‐1 and FGF‐3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF‐1 and FGF‐3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)‐7 and mitogen‐activated protein kinase kinase (Mek)/extracellular signal‐regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF‐1/‐3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP‐7 expression. The administration of FGF‐1/‐3‐neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer.

Potentially functional polymorphisms in the ERCC2 gene and risk of Esophageal Squamous Cell Carcinoma in Chinese populations

ERCC2 is indispensable for nucleotide excision repair pathway, and its functional polymorphisms may be associated with cancer risk. In a large case-control study of 1126 esophageal squamous cell carcinomas (ESCC) patients and 1131 controls, we genotyped two SNPs in ERCC2 (rs238406 G > T and rs13181 T > G) and assessed their associations with ESCC risk. We found a significantly elevated ESCC risk associated with the rs238406 T variant genotypes (adjusted OR = 1.30 and 1.24, 95% CI = 1.02–1.66 and 1.03–1.49 for TG and TG/TT, respectively, compared with GG), particularly in the subgroup of those smoked more than 16 pack-years. Multivariate logistic regression analysis suggested a possible multiplicative gene-environment interaction between rs238406 genotypes and smoking (Pinteraction = 0.026) on ESCC risk. Although no significant risk associations were observed for rs13181, further mini meta-analysis with our and 18 other published studies of 5,012 cases and 8,238 controls found evidence of an association between the rs13181 variant G allele and esophageal cancer risk (TG/GG vs. TT, OR = 1.17; 95% CI = 1.02–1.33). Interestingly, we consistently found a significant correlation between variant genotypes of these two SNPs and ERCC2 mRNA expression. These findings suggest that potentially functional SNPs in ERCC2 may contribute to ESCC risk.

Genetic variant of PRKAA1 and gastric cancer risk in an eastern Chinese population

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.

CASP7 variants modify susceptibility to cervical cancer in Chinese women

Polymorphisms in Caspase-7 (CASP7) may modulate the programmed cell death and thus contribute to cervical cancer risk. In this case-control study of 1,486 cervical cancer cases and 1,301 controls, we investigated associations between four potentially functional polymorphisms in CASP7 and cervical cancer risk and evaluated their locus-locus interaction effects on the risk. The genotype-phenotype correlation was performed by a generalized linear regression model. We found that the rs4353229 polymorphism was associated with cervical cancer risk (under a recessive model: crude OR = 1.20, 95% CI = 1.02–1.40). Compared with the TT genotype, the rs10787498GT genotype was associated with an increased cervical cancer risk (adjusted OR = 1.19, 95% CI = 1.00–1.41). Combination analysis showed that subjects with four putative risk genotypes had a 1.54-fold increased cancer risk, compared with those who carried three or less putative risk genotypes. We also observed significant locus-locus joint effects on the risk, which may be mediated by the polymorphisms regulating CASP7 mRNA expression. Subsequent multifactor dimensionality reduction and classification and regression tree analyses indicated that the CASP7 genotypes might have a locus-locus interaction effect that modulated cervical cancer risk. Out data suggest that CASP7 polymorphisms may interact to modify cervical cancer risk by a possible mechanism of regulating CASP7 mRNA expression.