Epidemiological Study On The Associations Among SNPs In TGF-β1 Pathway, Environmental Factors And Colorectal Cancer Risk

Backgrouds and ObjectivesColorectal cancer,with approximately 1.02 million new cancer cases and 529 000 deaths worldwide in 2002,is the second most prevalent cancer after breast cancer in the world.Colorectal cancer is especially common in the North America,Australia and Western Europe,while the incidence tends to be low in Africa and Asia.However, during the past decades,there have been remarkable changes in Asian countries in the incidence of colorectal cancer,the rates of which are increasing rather rapidly in countries where the risk was formerly low.The similar trend was observed in China as well.According to the Chinese National Cancer Database of 2003,colorectal cancer is one of the three cancers with most rapidly increasing incidence in the country between 1991 and 2003,and finally it ranks the third commonest malignant tumor.Most common human cancers,including colorectal cancer,have a multifactorial etiology involving complex interplay of genetic susceptibility and environmental exposures,and studying these factors together can improve the statistical power for detection of the underlying risk factors,give insight into their biologic effects and lead to public health strategies for prevention.It is widely accepted that environmental factors,such as diet,smoking,drinking and overweight,play key roles in the susceptibility to colorectal cancer development and progression.On the other hand, although numerous genes,in critical pathways of metabolism,DNA repair and apoptosis,implicated in low penetrance genetic predisposition to colorectal cancer have been identified,the polymorphisms in transforming growth factor-β(TGF-β) signaling pathway that contribute to the risk of colorectal cancer have not been fully demonstrated.The TGF-βsignaling pathway is involved in the control of several biological processes,including cell proliferation,differentiation,migration and apoptosis.Although there is accumulating evidence showing the importance of the TGF-β1 signaling pathway in carcinogenesis,no investigation has been carried out on the role of the polymorphisms in TGF-βpathway in relation to colorectal cancer in Chinese population.In this study,we hypothesized that the genetic polymorphisms in TGF-βsignaling pathway together with environmental factors were associated with colorectal cancer susceptibility.To verify this hypothesis,we conducted a population-based case-control study to evaluate the effects of TGF-β1 and its receptor gene polymorphisms on the risk of colorectal cancer in a Chinese population.Materials and MethodsThis population-based case-control study recruited eligible patients with histologically confirmed colorectal cancer reported by the cancer registry system as cases.Although there were no restrictions on patients' age,gender or tumor stage,only those patients who were free of metastases or other cancers were included in our study. Simultaneously,population controls who did not have a history of cancer were selected randomly and recruited from all permanent residents listed in the cancer registry system during the same period.All the participants were ethnic Han Chinese and residents in Jiashan County. At the beginning of investigation,written informed consent was obtained from each participant,and then they were face-to-face interviewed by trained personnel using a structured questionnaire,including demographic characteristics,personal habits (cigarette smoking,alcohol drinking,etc) and health factors(family history of cancer at any site including all first- and second-degree relatives of both genders,medical and dietary history,etc).In addition,a 5 ml venous blood sample was draw from each subject with the permission and then the genomic DNA was extracted from peripheral blood samples using modified salting-out procedure.For determination of the genetic polymorphisms of TGF-βsignaling pathway,Polymerase Chain Reaction- Restriction Fragment Length Polymorphism(PCR-RFLP) assay was performed.Unconditional logistic regression analysis was performed to calculate the odds ratios(ORs) with 95%confidence intervals(95%CIs) for estimating the association between certain genotypes and cancers with adjustment for the possible confounders. Stratified analyse and classification and regression tree model were used to explore potential low-order and high-order gene-gene and gene-environment interactions.ResultsThe demographic characteristics did not differ significantly between cases and controls.In smokers,those who get the smog into lung have a significantly increasing risk of rectal cancer(OR=2.15,95%CI=1.23～3.76).Tea drinking could significantly decreasd the colorectal cancer risk about 40%(OR=0.59,95%CI=0.42～0.82), especially the green tea has the protective effects on both colon and rectal cancer (OR=0.56,95%CI=0.35～0.89 and OR=0.60,95%CI=0.40～0.92,respectively).No polymorphism of G-800A,codon25,codon263 of TGF-β1 gene TGFβR2 A-364G was found in the study population and all the subjects carried wild-genotype. As compared with -509CC genotype,the -509CT genotype and TT genotype were associated with significantly decreased risk for colorectal cancer(OR=0.69, 95%CI=0.51～0.94 and OR=0.50,95%CI=0.36～0.71,respectively).TGF-β1 C-509T and codon10 polymorphisms were in strong linkage disequilibrium(D'=0.724, r2=0.431).Compared with the -509T/+29T haplotype,the -509C/+29C was associated with a significantly increased risk of colorectal cancer(OR=1.38,95%CI 1.13～1.68). LTBP-1L GA-CC was significantly associated with the colorectal cancer susceptibility in the recessive model and the varited genotypes could significantly increase the risk of colon caner and rectal cancer(OR=1.48,95%CI=1.02～2.16 and OR=1.58, 95%CI=1.11～2.25,respectively).Complex gene-gene and gene-enviornmental interactions were found according to the results of stratified analyse and classification and regression tree model.LTBP-1L GA-CC had combined effects with TGF-β1 C-509T,TGF-β1 codon10 and TGFβR1 int7G24A,the high risk genotypes carriers had significant increased risk suffering colorectal cancer comparing with those who carried low risk genotypes.Several combined effects were also found between tea drinking and SNPs.ConclusionsThe frequency patterns of polymorphisms in TGF-βsignaling pathway vary greatly among different ethnic groups.In this pathway,TGF-β1 C-509T is the most important SNP affecting the susceptibility to colorectal cancer independently or together with LTBP-1L GA/CC and other SNPs.There are complex interactions of genetic susceptibility and environmental exposures,CART might be a useful tool for exploring the high-order interactions.