| Background and ObjectiveColorectal cancer is one of the most common malignant tumors of human alimentary tract. lts incidence rate and mortality rate rank the forefront among all common cancers both domestic and worldwide. Although China is a low-incidence area, its incidence rate and mortality rate in China show a yearly increasing trend with changes in dietary structures and life styles of residents and prolongation of per capita expectancy in recent years.The accumulated evidence suggest the occurrence of colorectal cancer is a multi-factor involved and multi-stage process, which is mainly influenced by environmental exposures. Epidemiological studies indicated common environmental exposures related to the susceptibility of colorectal cancer are high-fat and/or low-fiber diet, fried, fumed, or baked food, low intakes of vegetables and fruits, smoking, drinking, low physical activity or long sedentary time.Associations between folate metabolism and cancers development showed more and more importance in last decade. Folate metabolic process includes two main branches, biological synthesis of nucleic acid and methylation process. Disturbances of folate metabolism can cause abnormal DNA synthesis and DNA methylation. Folate, methionine, VitB2, VitB6, and VitB12 are primary nutrients taking part in folic acid metabolism, and methylenetetrahydrofolate(MTHFR), methionine(MTR), methionine synthase reductase (MTRR), and thymidylate synthase (TS) are primary enzymes enrolling in folic acid metabolism. The level or activity changes of the above-mentioned nutrients or metabolic enzymes might influence folate metabolism, cause inbalance between biological synthesis of nucleic acid and methylation reaction, and take part in colorectal carcinogenesis.Major defects in past etiology study may be: first, most study was carried out independently and separately which lack of comparability among mass of results; second, little was known about the linkage between cancer development and some special polymorphism in different ethnics demanding the necessity to get more evidence about it; third, it was hard to get absolute conclusion with single aspect taken into consideration, above all, study on the role of diet-environment-gene interaction in colorectal cancer is still rare.To carry out lagre scale cooperative population studies in different ethnics with standard methodology which integrated epidemiology, nutriology, molecularbiology and bioinformatics will help overcoming the problems remaining in CRC ,concluding clearer etiological evidence. So, a collaborative study was carried out in China, Japan and Korea for the purpose of revealing dietary protective / risk factors and relationship between genetic susceptibility and colorectal cancer in eastern Asian populations. The present study is part of the study with the aim to examine the effects of environmental and dietary factors, genetic susceptibility and their interactions on colorectal cancer in Benxi population.The purpose of the case-control study is to explore distributions of gene polymorphisms of folate metabolic enzymes in a natural population and associations between these polymorphisms and susceptibility to colorectal cancer at a population level, and further to analyze the role of gene-gene and gene-environment interactions in the development of colorectal cancer.Materials and MethodsThe cases were 300 patients who were histologically diagnosed as having CRCs between January 2003 and June 2005 at Benxi country steel group center hospital and not having any earlier history of cancer. Controls were inpatient who visited Benxi country steel group Center Hospital during the same period as cases and were confirmed to have no cancers and no prior history of cancers. Controls were randomly selected and matched for age and sex strata to cases .Field data were obtained by an epidemiological questionnaire investigation. The investigation contents mainly included common state , life styles and habits, dietary habits and categories,and past disease histories. Intake quantities of all common kinds of foods were obtained by asking subjects single time intake and intake frequencies of foods.A sample of venous blood (5m1) was taken from every subject. Genomic DNA was extracted from karyocyte by Promage Winzard Genomic DNA Extract . Genotypes of MTHFRC677T,A1298C,MTR A2756G,MTRR A66G ,TS3'-UTR and TS5'-UTR polymorphisms were determined by PCR-restriction fragment lengthen polymorphism method.Genotype of CBS844ins68 polymorphism was determined by directly electrophoreses of PCR products on agarose gels.Distributional characteristics of cases and controls were analyzed by X2 test, and the non-conditional Logistic model was applied to estimate the ORs delaminated by age, sex, smoking and drinking for colorectal cancer of related study factors ,adjusted for age sex status of smoking and drinking where appropriate.Chi-square trend test was applied to analyze dose-reaction relationship, subjugation model to ananlyze gene-gene and gene-environment interactions,likelihood test for calculating P values . All statistical analysis was processed by SPSS 13.0 for windows and Microsoft Excel 2007.Results1. Related environmental exposures and colorectal cancer1.1 For demographic factors, Subjects with education degrees of college and above, Family cancer history are significant risk factors of CRC .1.2 For smoking and drinking, long period drinkers had a statistically significant increased risk of CRC with OR value of 1.54 (95%Cl, 0.83-2.86). Smoking was associated with CRC at the OR of 1.76(95%CI,1.12-2.76).Passive smokers were at statistically significant increased risks of CRC with OR values of 1.87 (95%CI,1.09-3.19) .The drinkers without smoking history showed significantly increased risk to CRC with the OR value of 1.69(95%CI,1.03-2.78).1.3 For dietary factors,retinol,VitC,dietary total fibre,fruit,bean and its derivates,leafy vegetables including Cauliflover,cabbage and garlic are strong protective factors to CRC,as also potassium intake .Middle level of MUFA intake increased the risk of CRC significantly(OR=2.65, 95%CI,1.47-4.57)2. Gene polymorphisms of folate metabolic enzymes and colorectal cancer2.1 MTHFR-677CT/1298AC genes were associated with significantly increased risk of CRC(OR=2.32,95%CI, 1.10-4.92)2.2 MTRR-66AG,66GG and 66G allele are associated with increased risk of CRC(OR=1.49,95%CI, 1.02-2.18; OR=2.49,95%CI, 1.35-4.60 and OR=1.62,95%CI, 1.13-2.32, respectively).2.3 TS5'-UTR 2R/2R showed decreaed risk to CRC with the OR value of 0.35(95%CI, 0.12-0.98)3. Gene-gene interactions and colorectal cancer3.1 The interaction between MTHFR C677T and MTRR A66G showed a decreased risk of CRC with the ORint value of 0.46,and its likelihood test P is 0.046.Individuals carrying MTHFR-677CC showed increased risk of CRC eith the OR value of 2.84(95% CI,1.43-5.66), when also carrying MTRR-66AG or GG;Individuals carrying MTHFR-677CT or TT allele ,showed increased risk of CRC with the OR value of 1.93(95%CI,1.01-3.68)when also carrying MTRR-66AA,and 2.34(95%CI,1.33-4.14)when also carrying MTRR-66AG or GG allele..3.2 Individuals with MTR-2756AA,showed increased risk of CRC with the OR value of 1.62(95%CI,1.43-5.66), when also carrying MTRR-66AG or GG.3.3 Individuals with MTRR-66AG or GG allele showed increased risk of CRC with the OR value of 3.24(95%CI,1.22-8.58), when also carrying TS5'-UTR 3Rg/3Rg3.4 TS5'-UTR 3Rg/3Rc+3Rg/2R +3Rc/2R+2R/2R +3Rc/3Rc combined gene with TS3'-UTR ins6 allele was associated with decreased the risk of CRC with the OR of 0.47(95%CI,0.22-1.19)4. Gene-environment interactions and colorectal cancer4.1 Smoking-gene and CRC : MTRR A66G polymorphism and smoking showed synergistic effect on CRC. In non-smokers,the risk of CRC in 66G allele carrier was 1.72-fold to that in 66AA gene carrier ;While in smokers ,this increased to 2.08-fold,which means negative interaction between MTRR A66G and smoking (ORint=0.78, likelihood test P=0.04).Interactions were found between the extent of smoking and MTHFR C677T,A1298C,MTR A2756G,MTRRA66G,TS5'-UTR and TS3'-UTR.Refered to non-smokers,the risk of CRC increased by 2.09(95%CI,1.07-4.04) in smokers lower than 16 pack year with MTHFR-677T allele ,while MTRR-66G allele 2.91(95% CI,151-5.62). In MTHFR-1298AA gene and TS3'-UTR del6/del6 significantly decreased the risk CRC by 0.37 (95%CI,0.17-0.80) and 0.17(95%CI, 0.05-0.56), respectively .Negative interation between smoking years and MTRR A66G was found (ORint=0.70, likelihood test P=0.002).In smokers ,smoking less than 26years,MTRR-66G increased risk of CRC by 4.55(95%CI,1.98-10.43).4.2 Drinking-gene and CRC: Interation between drinking and MTRR A66G was found (ORint=1.07, likelihood test P=0.001). Negative interation between drinking extent and MTHFR A1298C or was found ,while interation between drinking extent and MTHFR C677T,MTR A2756G or TS5'-UTR was also found ;The risk of CRC increased by 3.98(95%CI,1.54-10.24) in drinkers lower than 20 years with MTRR-66G allele ,while In drinkers lower than 20 years with MTHFR-677AA and 1298AA gene significantly decreased the risk CRC by 0.24(95%CI,0.10-0.58)and 0.58(95%CI,0.34-0.98 ),respectively.4.3 Drinking-smoking-gene and CRC: In drinkers,the risk of CRC in smokers and MTHFR-677T allele increased by 4.61(95%CI,1.57-13.46) ,when also carrying MTRR-66G 4.06(95%CI,1.53-10.79).5. gene-meal interactions and colorectal cancer5.1 The interaction between MTHFR C677T and VitB12 or Methionine was showed , the ORint value of 1.07 and 1.12 ,respectively. In high VitB12 and middle,high Methionine intake groups, the risk of CRC in MTHFR-677CC and 677T allele significantly decreased . In middle VitB2 and high folate intake groups, the risk of CRC in MTHFR-677T allele significantly decreased .5.2 The interaction between MTHFR A1298C and VitB12 or folate was showed. In high VitB12 intake groups, the risk of CRC in MTHFR-1298AA and 1298C allele significantly decreased .5.3 In high VitB12 intake groups, the risk of CRC in MTR-2756AA and 2756G allele significantly decreased .5.4 The interaction between MTRR A66G and VitB2 or nicacid or VitB6 or folate or Methionine were showed, the ORint value of 1.46,1.19,1.10 and 1.07,respectively. In high VitB12 intake groups, the risk of CRC in MTHFR-1298AA and 1298C allele significantly decreased. while negative interation and VitB12 intake, the ORint value of 0.79. In lower,high VitB12 intake groups and in high folate,methionine intake groups, the risk of CRC in MTRR-66G allele significantly decreased . the risk of CRC in MTR-2756AA and 2756G allele significantly decreased . In high VitB12 intake groups, the risk of CRC in MTRR-66AA significantly decreased .5.5 The interaction between TS3'-UTR and VitB12 was showed, the ORint value of 0.70. In high VitB12 intake groups, the risk of CRC in TS3'-UTR del6/del6 and ins6 allele significantly decreased .5.6 The interaction between TS5'-UTR and VitB2,folate and methionine was showed, the ORint value of 1.35,1.41 and 1.47,respectively. In middle nicacid intake group, the risk of CRC in TS5'-UTR 3Rg/3Rc+3Rg/2R +3Rc/2R+2R/2R +3Rc/3Rc combine genes was 2.65-fold to than 3Rg/3Rg gene carrier .Conclusions1. The risk factors of CRC are education degrees of college and above, individual histories of cancer, passive smoking, MTHFR-677CT/1298AC combine genotype and MTRR -66G allele .2. The protective factors of CRC are often eating vegetable,fruit and higher retinol or VitC or dietary total fibre intake, TS5'-UTR 2R/2R genotype.3. There are interactions between MTHFR C677T and MTRR A66G polymorphisms, smoking history and MTRR A66G, smoking duration and MTHFRC677T,smoking duration and MTRRA66G, smoking extent and MTHFRC677T , smoking extent and MTHFR A1298C, smoking extent and MTRA2756G, smoking extent and MTRRA66G, smoking extent and TS3'-UTR, smoking extent and TS5'-UTR ,drinking history and MTRR A66G, drinking duration and MTHFRC677T,A1298C, drinking duration and MTRA2756C, drinking duration and MTRRA66C, drinking duration and TS5'-UTR polymorphism, dietary VitB2 intakes and MTRRA66G , dietary VitB2 intakes and TS5'-UTR, dietary nicacid intakes and MTRRA66G, dietary VitB6 intakes and MTRRA66G, dietary VitB12 intakes and MTHFR C677T or A1298C, dietary VitB12 intakes and MTRRA66G , dietary VitB12 intakes and TS3'-UTR polymorphism ,dietary folate intakes and MTHFR A1298C, dietary folate intakes and MTRRA66G, dietary folate intakes and TS5'-UTR, dietary methionine intakes and MTHFRC677T, as welL as dietary methionine intakes and MTRR A66G or TS5'-UTR. Gene-gene and gene-environment interactions in folate metabolic process can jointly influence individual susceptibility of CRC.
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