| Background and ObjectiveColorectal cancer, including colon cancer and rectum cancer, is one of common malignant tumors of alimentary tract. Its incidence rate and mortality rate rank front 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 of dietary structures and life styles of residents and prolongation of per capita expectancy in recent years. The occurrence of colorectal cancer is a multi-factor involved in and multi-stage process, which is mainly influenced by environment exposures. Epidemiological studies concluded common environment exposures related with 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, and histories of mucoid stool and bowel polyps.Associations between one-carbon metabolism and cancers were attached more and more importance in last decade. One-carbon metabolic process includes two main branches, biological synthesis of nucleic acid and methylation reaction. Disturbances of one-carbon metabolism can cause abnormal DNA synthesis and DNA methylation. Folate, methionine, VitB2, VitB6, and VitB12 are primary nutrients taking part in one-carbon metabolism, and methylenetetrahydrofolate (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and thymidylatesynthase (TS) are primary enzymes enrolling in one-carbon metabolism. The level or activity changes of the above-mentioned nutrients or metabolic enzymes might influence one-carbon metabolism, destroy the balance between biological synthesis of nucleic acid and methylation reaction, and take part in colorectal carcinogenesis.The purpose of the cohort-based case-control study is to explore distributions of gene polymorphisms of one-carbon metabolic enzymes in a nature population and associations between these polymorphisms and the susceptibility to colorectal cancer on a population level, and further analyze the role of gene-gene and gene-environment interactions in the development of colorectal cancer.Materials and MethodsA colorectal cancer screening cohort in Jiashan County, Zhejiang Province with 64693 persons enrolled in which covered 10 towns and was established during 1989 to 1990 was treated as the study population. 207 prevalent patients of colorectal cancer diagnosed from May 1990 to May 2005 in the cohort made up of the case group. According to age and sex distributions of the cohort, 950 persons were selected out as controls by stratified sampling, and actually 847 persons accepted the investigation, 841 of which had both questionnaires and blood samples. By means of simple random sampling method, a control sample with 414 persons, a 2-folded sample size of the case group was selected from these 841 controls and treated as the control group for data analysis.Field data were obtained by an epidemiological questionnaire investigation. The investigation contents mainly included demographic factors, 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 per time intake and intake frequencies of foods, and uniform-made food models were used to assist the food investigation.A sample of venous blood (5ml) was taken from every subject. Genome DNA was extracted from leucocytes by improved salt out method. Genotypes of MTHFRC677T, A1298C, MTRA2756G, MTRRA66G and TS3'-UTR polymorphisms were detected by PCR-restriction fragment lengthenpolymorphism method. The genotype of TS5'-UTR polymorphism was detected by directly electrophoresing PCR products on agarose gels.All questionnaires were uniformly coded, and then input into computer for double times. After revising and correcting the data, statistical analysis was carried out. Distributional characteristics of qualitative variables between cases and controls were analyzed by^2 test, and a non-conditional Logistic model was used for estimations of OR values for colorectal cancer of related study factors, chi-square trend test for judging dose-reaction relationship, likelihood test for calculating P values of gene-gene and gene-environment interactions. All statistical analysis was processed in softwares of SPSS 13.0 for windows and Microsoft Excel 2003.Results1. Related environmental exposures and colorectal cancerFor demographic factors, colon cancer was more incident in those aged over 62 years old who were at statistically significant increased risks with OR values of 2.34 (95%C7, 1.17-4.68) and 2.04 (95%C7, 1.00-4.17). Subjects with education degrees of senior high school and over also had a statistically significant increased risk of colon cancer with an OR value of 2.31 (95%C7, 1.05-5.08), however, famers were at a statistically significant decreased risk of colon cancer with an OR value of 0.56 (95%C7, 0.34-0.90).For disease histories, subjects with histories of bowel polyps, colitis and schistosomiasis had statistically significant increased risk of both colon and rectum cancers with OR values of 17.38 (95%C7, 3.34-90.42), 18.21 (95%C7, 3.82-86.71), 2.75 (95%C7, 1.02-7.43), 3.36 (95%C7, 1.38-8.16), 4.18 (95%C7, 2.37-7.36) and 3.09 (95%C7, 1.91-4.99) respectively.For smoking and dringking, tipple drinkers had a statistically significant increased risk of colon cancer with an OR value of 2.50 (95%C7, 1.20-5.23). Passive smokers were at statistically significant increased risks of both colon and recum cancers with 07? values of 2.14 (95%CI, 1.11-4.14) and 1.92 (95%C7, 1.09-3.37) respectively.For dietary factors, subjects prefer to hard foods had a statistically significant increased risk of rectum cancer with an OR value of 2.29 (95%C/, 1.29-4.05). High intakes of Chinese cabbages were related with a statistically significant decreased risk of rectum cancer with an OR cvalue of 0.98 (95%C7, 0.96-1.00), and high intakes of oranges were related with a statistically significant decreased risk of colon cancer with an OR value of 0.91 (95%C7,0.84-0.98).For energy and one-carbon related nutrients, middle intake of energy was related with a statistically significant increased risk of colon cancer with an OR value of 1.84 (95%CI, 1.03-3.31), and middle and high intakes of energy were related with statistically significant increased risks of rectum cancer with OR values of 2.11 (95%C7, 1.20-3.70) and 1.91 (95%C7, 1.10-3.31) respectively. High intake of VitB2 was associated with a statistically significant decreased risk of rectum cancer with an OR value of 0.50 (95%C7, 0.25-0.97).2. Gene polymorphisms of one-carbon metabolic enzymes and colorectal cancerMTR2756G allele was associated with statistically significant increased risks of colon and rectum cancer with OR values of 2.01 (95%C/, 1.12-3.60) and 1.86 (95%C7, 1.08-3.21) respectively. MTRR66G allele was associated with a statistically significant increased risk of rectum cancer with an OR value of 1.93 (95%C7, 1.21-3.10).3. Gene-gene interactions and colorectal cancerP for interaction between TS5'-UTR and 3'-UTR polymorphisms were less than 0.01 (colon cancer). Carriers with 3R/3R genotype and ins6 allele and carriers with del6/del6 genotype and 3R allele had statistically significant decreased risks with OR values of 0.46 (95%C7, 0.25-0.84) and 0.23 (95%CY, 0.08-0.69) respectively. '4. Gene-environment interactions and colorectal cancer4.1 With smoking P for interaction between MTHFRC677T and smoking history equaled 0.03 (colon cancer). Among subjects without smoking histories, 677T allele carriers had a statistically significant decreased risk of colon cancer with an OR value of 0.23 (95%C7, 0.05-1.13). P for interaction between MTHFRC677T and smoking duration was 0.03 (colon cancer) and 0.03(rectum cancer) respectively. Among subjects whose smoking duration<32years, carriers of 677TT genotype was associated with a statistically decreased risk of rectum cancer with an OR value of 0.16 (95%C/, 0.04-0.60). Among non-smokers, carriers of 677T allele was associated with a statistically decreased risk of colon cancer with an OR value of 0.24 (95%C7, 0.05-1.20).4.2 With drinking P for interaction between TS3'-UTR polymorphism and drinking history equaled 0.03 (colon cancer). Among non-drinkers, ins6 carriers had a statistically significant decreased risk of colon cancer with an OR value of 0.46(95%C7, 0.25-0.82). P for interaction between TS5'-UTR and drinking duration equaled 0.02 (rectum cancer). 2R allele carriers whose drinking duration>30 years had a statistically significant increased risk of rectum cancer with an OR value of 2.81 (95%C7, 1.01-7.83). P for interaction between TS3'-UTR polymorphism and drinking duration equaled 0.03 (colon cancer) and 0.04 (rectum cancer) respectively. Among non-drinkers, ins6 allele carriers had a statistically significant decreased risk of colon cancer with an OR value of 0.48 (95%C7, 0.27-0.84).4.3 With VitB6 intakes P for interaction between MTRA2756G and VitB6 intake equaled 0.05 (colon cancer). Among subjects with low and middle VitB6 intakes, 2756G allele carriers had increased risks of colon cancer with OR values of 2.85 (95%C7, 0.95-8.52) and 3.46 (95%C7, 1.34-8.93) respectively.4.4 With VitB12 intakes P for interaction between MTHFRC677T and VitB12 intake equaled 0.04 (rectum cancer). In high VitB12 intake group, 677T allele carriers had a statistically significant decreased risk of rectum cancer with an OR value of 0.49 (95%C7, 0.23-1.06). P for interaction between MTRA2756G and VitB12 intake equaled 0.02 (rectum cancer). In low VitB12 intake group, 2756G allele carriers had a statistically significant increased risk of rectum cancer with an 07? value of 4.26 (95%C7, 1.73-10.52).4.5 With folate intakes P for interaction between MTHFRA1298C and folate intake were 0.03 (colon cancer) and 0.02 (rectum cancer) respectively. Subjects with low folate intakes and carrying 1298C allele had an increased risk of colon cancer with an 07? value of 2.12 (95%C7,0.87-5.17).4.6 With methionine intakes P for interaction between MTHFRC677T and methionine intake was 0.01 (colon cancer). Subjects with low methionine intakes and carrying 677T allele had a statistically significant increased risk of colon cancer with an OR value of 4.06 (95%C7, 1.44-11.45). P for interaction between TS3'-UTR polymorphism and methionine intake were 0.04 (colon cancer) and 0.03 (rectum cancer). Ins6 allele carriers in middle methionine intake group and del6/del6 genotype carriers in high methionine intake group had statistically significant decreased risks of colon cancer with OR values of 0.41 (95%C7, 0.16-1.05) and 0.37 (95%C7, 0.12-1.13) respectively.ConclusionsAging over 62 years old, education degrees of senior high school and over, individual histories of bowel polyps, colitis and schistosomiasis, tipple, passive smoking, high-energy intakes, MTHFR677CT genotype and MTR2756G allele are risk factors of colon cancer, and farmers and often eating oranges are protective factors. Individual histories of bowel polyps, colitis and schistosomiasis, passive smoking, preference to hard foods, high-energy intakes, MTR2756G allele and MTRR66G allele are risk factors of rectum cancer, and often eating Chinese cabbages and high intakes of VitB2 are protective factors. There are interactions between TS5'-UTR and 3'-UTR polymorphisms, smoking history and MTRRA66G, smoking duration and MTHFRC677T, smoking duration and MTRRA66G, smoking duration and TS5'-UTR, drinking history and TS3'-UTR, drinking duration and MTHFRC677T, drinking duration and MTRA2756G, drinking duration and MTRRA66G, drinking duration and TS5'-UTR polymorphism, drinking duration and TS3'-UTR, dietary VitB6 intakes and MTRA2756G, dietary VitB12 intakes and MTHFRC677T, dietary VitB12 intakes and MTRA2756G, dietary folate intakes and MTHFRA1298C, dietary folate intakes and MTRA2756G, dietary folate intakes and MTRRA66G, dietary folate intakes and TS3'-UTR, dietary methionine intakes and MTHFRC677T, as well as dietary methionine intakes and TS3'-UTR. Gene-gene and gene-environment interactions in one-carbon metabolic process can jointly influence individual susceptibility of colon and rectum cancer.
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