Molecular Epidemiological Study On Transforming Growth Factor β(TGFβ) Signaling Pathway And Gastric Cancer

Gastric cancer is one of the major causes of cancer-related deaths worldwide,ranking the second for men and the fourth for women in 2002, although both the incidence and mortality of gastric cancer have been declining in recent years.The exact mechanisms of gastric cancer development remains unclear,although multiple factors have been proposed to play a role in gastric carcinogenesis,including diet, exogenous chemicals from tobacco smoke,infectious agents such as the Helicobacter pylori(H.pylori).Exposures to the above exogenous risk factors may attribute to gastric cancer risk,and the host susceptibility may also play an important role in of gastric cancer development.The transforming growth factorβ(TGF-β),a pluripotent cytokine distributed widely in almost all human cells,plays a dual role in cancer development: suppressing the early stage tumor growth but promoting tumor progression and metastasis.Disrupted TGFβsignalling is involved in the development of various types of cancer.Concentrations of TGFβ1 and its receptor TGFβRâ…¡in plasma have been correlated with the development of certain forms of cancer,including gastric cancer.TGFβRI has a rate-limiting role in the signaling pathway.Any quantitative and qualitative changes in TGFβRâ… will be expected to affect TGFβ-mediated growth inhibition in normal epithelial cells.Tumor cells frequently lose responsiveness to TGFβ-mediated growth inhibition due to disruption in the TGFβsignaling pathway.Partâ… Functional Polymorphisms in the TGFB1,TGFBR2 Genes and Risk of Gastric Cancer in a Chinese Population[Objective]Based on the important role of both TGFB1 and TGFBR2 in the gastric carcinogenesis and the functional SNPs identified in these two genes,we hypothesized that these functional variants of TGFB1 and TGFBR2 were associated with gastric cancer susceptibility.[Methods]We genotyped C-509T and Leu10Pro polymorphisms in TGFB1 and G-875A variant in TGFBR2 using the PCR-RFLP assay in a case-control study including 675 gastric cancer cases and 704 healthy controls in a Chinese population.[Results]We found that the variant alleles of the promoter polymorphisms of TGFB1 C-509T and TGFBR2 G-875A were associated with a significantly decreased risk of gastric cancer(adjusted OR=0.65, 95%CI=0.52-0.82 for-509CT/TT and adjusted OR=0.67,95% CI=0.53-0.85 for-875GA/AA respectively).Furthermore,subjects with both variant genotypes of the TGFB1 C-509T and TGFBR2 G-875A were associated with a significantly 56%decreased risk of gastric cancer (adjusted OR=0.44,95%CI=0.32-0.62).[Conclusion]These findings indicated that functional variants in the promoter of TGFB1 and TGFBR2 might contribute to gastric cancer susceptibility.Partâ…¡Association of Tagging SNPs in the Transforming Growth FactorβReceptor Type 1 Gene and Risk of Gastric Cancer[Objective]To comprehensively investigate the roles of the polymorphisms in TGFBR1 in the development of gastric cancer,we conducted a case-control study including 675 gastric cancer cases and 704 age and sex frequency-matched cancer-free controls.[Methods]We choose SNPs from the HapMap on TGFBR1 polymorphisms based on the HapMap block region coverage,minor allele frequency(MAF),and functional relevance.We selected and genotyped 5 tagging SNPs in TGFBR1 gene to test the hypothesis that genotypes/haplotypes of the TGFBR1 gene may contribute to susceptibility to gastric cancer.[Results]The logistic regression analysis revealed that the rs10512263 CT heterozygote was associated with a significantly increased risk of gastric cancer(adjusted OR=1.28,95%CI=1.01-1.61)compared with the TT wild-type homozygote.The variant genotypes of the rs6478974 A allele was associated with significantly decreased risk of gastric cancer in a dose-response manner with the increase of the number of A allele(P for trend=0.043).Subjects carrying rs10512263 CT/CC genotype were associated with an increased GC risk among non-smokers and individuals with negative H.pylori infection(adjusted OR=1.50,95% CI=1.13-2.00;x_MH²=4.63,P=0.031;adjusted OR=1.57,95% CI=1.04-2.36,x_MH²=4.16,P=0.041).The risk of gastric cancer was significantly decreased among subjects carrying the haplotype "CATGA" compared to those carrying the most common haplotype "CTTGA"(OR =0.65,95%CI=0.46-0.91).By using multifactor dimensionality reduction (MDR)analysis,genotypes of TGFB1 C-509T,TGFBR2 G-875A and TGFBR1 rs10512263 are the three factors included in the MDR-defined best model on gastric cancer risk.When these variables were combined and dichotomized,we found that subjects carrying the combined risk stratum had a significantly 2.24-fold(95%CI=1.81-2.78,P=1.47×10^-13) increased risk for gastric cancer.[Conclusion]Our findings suggested that genetic variants in TGFβsignalling pathway may modulate the risk of gastric cancer and larger studies and functional studies are needed to confirm our findings.