Study On Role Of Environment-Dietary Factors, Genetic Susceptibility And Their Interaction In Colorectal Cancer Risk

Background:Colorectal Cancer (CRC) is one of the most common malignant cancers. In 2004, there were near 6 million CRC sufferers in the whole world and more than 620 000 people died of it, the morbidity and mortality ranked 4 and 3 in all cancers respectively in all cancers. Incidence rate varied approximately 20 folds when compared the highest rate in developed countries with the lowest rate in many developing countries such as India and Africa. In China, the CRC onset had a sharply increasing during the past decades with the development of economy and the trend of "western" life styles including diets. It was suspected there will be a markedly elevation in CRC morbidity and mortality in future 20~30 years and it will become an "emergency cancer" in China.Etiology study suggested that, except less than 10% of CRC due to inherited genes mutation, most sporadic CRC related to environment factors especially diets. So the CRC was thought to be the results of a complicated multistep process undergone the impact of diets, environment, genes and, if there be, their interaction in a long periods.Lots of epidemiologic study on the relationship between environmental and dietary factors, lifestyles and CRC occurrence got inconsistently results. Dietary fat, protein, several mines, vitamins and smoking, alcohol drinking are thought closely relate to CRC, but again lack of enough evidence to confirm their effect on cancer. Someone always seemed be "easily" influenced even exposed to same environment, and the polymorphic genes encoding enzymes involving in metabolism of diets and in exposure response is thought to cause such susceptibility status of colorectal neoplasia. Most relative studiesfocused on metabolizing enzymes genes with a high prevalence genetic polymorphisms including glutathione-S-transferase (GST), N-actyltransferase (NAT), methionine synthase (MS), methylenetetra-hydrofolate redutase (MTHFR) which involving in stage II and folate metabolism respectively, the results still inconsistent.The interaction between extra-and inner factors and the way how they caused colorectal cancer still kept obscure.Major defects in past etiology study may be: first, most study was carried out independently and separately so that lack of comparability among mass of results; second, little was known about the linkage between cancer and some special polymorphism in different ethnics made the necessity to get more evidence about it; third, it was hardly get absolute conclusion with only single aspect taken into consideration, but study on role of diet-environment-gene interaction in colorectal cancer is still rare.Since 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 causes decision and providing evidences for clear etiological conclusion. So, a collaborative study was processed 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 such a huge study with the aim to examine the effect of environment and dietary factors, genetic susceptibility and their interaction on colorectal cancer in Chongqing population.Objective:To reveal the colorectal cancer dietary protective / risk factors, and to examine the relation between relative genes polymorphisms and colorectal cancer, and the effect of environment-diet-gene interaction on colorectal cancer in Chongqing population.Method:1. To develop a semi-quantitative food frequency questionnaire (SQFFQ) as a dietary intake assess tool while examining relation between nutrients and disease in Chongqing adults;2. In the hospital-based case-control study comprising 478 cases (colon 185, rectum 293)and 838 controls with gender, age of 5 years and living place matched, informations about diet and life styles was collected in manner of investigator-interviewing.3. Extracting DNA from peripheral vein blood, by using Restriction Fragment LengthPolymorphism and Multiplex-PCR methods, analyses the polymorphisms of folate metabolism-relative MTHFR gene C677T, A1298C, MS gene A2756G; fat metabolism-relative PPARy2 gene Prol2Ala, C161T, CD36 gene C478T; phase II metabolism-relative GSTMl, GSTTl gene sites.4. Using Odds ratio and its 95% confidence interval to represent the risk of disease 0Result:1. The nutrition coverage percentage of SQFFQ, which composed by 119 selected foods, is 94.9% and 93.6% in Chongqing rural and urban area respectively, with a good validity and reproducibility shown in following tests.2. Family cancer history, spirit hurt, bad human relation and excessively emotion self-control significantly elevated risk of CRC;3. In life styles: alcohol drinking increased the risk of CRC but the time of drinking and drinking level did not shown association with increasing risk; smoking, tea consumption, labor density, sleeping time and physical exercise did not associated with CRC significantly;4. Several vitamins, including carotene, retinol and vitamin C, and dietary total fibre, leafy vegetables sharply decreased the CRC risk significantly; Other nutrients such as fat, protein, carbohydrate and important doubtable foods such as cereals, meats and dairies, eggs all did not significantly associated with CRC;5. Gene polymorphisms and CRC: ? MS gene 2756G genotype significantly elevated risk of retum cancer but not associated with colon cancer, C677T and A1298C polymorphism of MTHFR gene shown no correlation with CRC risk; (2)PPARy2 gene 161T genotype only significantly elevated risk in retum cancer but not in colon cancer, CRC risk did not changed significantly for the 161TT genotype and Pro 12Ala polymorphism, risk associated to CD36 gene did not be analysed for the reason of very low 478T genotype frequency (0.0034) in study subjects; (3) Deletion of GSTMl and GSTTl genes did not contribute to CRC risk at statistically significant extent;6. Interaction between polymorphisms correlate to CRC risk: By using wild types as reference, interaction of polymorphisms in genes involving in same metabolism path way did not associated to CRC risk significantly. But interaction of polymorphisms in genes involving in different metabolism path way associated to CRC risk significantly. Interaction between MS gene 2756G genotype and fat-metabolize gene, GSTMl and GSTTl gene can respectively markedly increase rectum cancer risk with statistical significance, but no correlation to colon cancer; Interaction between PPARy2 gene 161T genotype and MS gene 2756G genotype increased rectum cancer risk but interaction between 161T genotype and GSTMl, Tl gene, null or positive, all made a significant elevation of colon cancer risk respectively.7. Impact of diet-gene interaction on CRC risk: High intake of several vitamins and leafy vegetables can decrease CRC risk significantly in individuals with MS2756G genotype but to a less extent in individuals with 2756A genotype; Fat, SFA, MUFA, PUFA, at the highest quartile intake level, sharply increase the CRC risk in individuals with PPARy2 gene 12Ala genotype; dietary fat and meats intake had no association to CRC risk even under interaction with PPARy2 gene 161Tgenotype, GSTMl and Tl gene deletion.8. Impact of environment-gene interaction on CRC risk: Smoking can significantly increaseCRC risk in individuals with mutative polymorphic sites in genes involving in folate metabolism, that means MTHFR 677T, 1298C or MS 2756G genotype, but did not associated with CRC risk in individuals carrying wild genotypes; In subgroups with MTFHR gene 677T, 1298C, MS gene 2756, PPARy2 gene 161 sites mutated and GSTMl null or GSTTl positive genotypes, alcohol drinking increase CRC risk significantly, but shown no association with CRC risk in subgroups with other genotypes.9. Impact of environment-diet-gene interaction and CRC risk: Compared with never smokers in wild genotypes, the interaction between smoking and wild or mutative genotype increased CRC risk, though not all situations is significant, in subgroup at high fat intake level but to a less extent in subgroup at low fat intake level. Compared with never drinker in wild genotypes, the interaction between drinking and wild or mutative genotypes increase CRC risk, though not all situations is signicant, in both subgroups at high or low fat intake level but to a less extent in subgroup at high fat intake level;Conclusion:1. The developed SQFFQ is proved to be a good diet access tool in Chongqing adults while examining the relationship between dietary intake and CRC;2. Family cancer history, spirit hurt, bad human relation and emotion excessively control are significant risk factors of CRC; alcohol drinking is risk factor of CRC but smoking and tea consumption are not associated to CRC significantly;3. There still need more evidence to confirm CRC dietary risk factors. Those foods used to be thought to have close correlation to CRC such as fat and meats did not show associations with CRC in present study. But we can confirm several vitamins, including carotene, retinol and vitamin C, and total dietary fibre, leafy vegetables as CRC dietary protective factors;4. Gene polymorphisms and CRC: MS gene 2756G genotype or PPARy2 gene 161T genotype probably is susceptible factors of CRC; Other genetic polymorphisms, such as MTHFR gene 6111, 1298C, PPARY2 gene Prol2Ala and GSTMl, GSTTlgene null/Positive, show no association with CRC risk. Interaction between polymorphisms also did not significantly associated with CRC risk;5. Diet-gene interaction plays a role in CRC risk: High intake of several vitamins and leafy vegetables can decrease CRC risk significantly in individual with MS2756G genotype; but dietary Fat, SFA, MUFA, PUFA can sharply increase the CRC risk in individuals with PPARy2 gene 12Ala genotype;6. Environment-gene interaction plays a role in CRC risk: Whether smoking or drinking to be a CRC risk factor depend on the mutation of folate-metabolisma genes or deletion of GSTMl or GSTTlgene;7. Environment-diet-gene interaction may effect risk of CRC significantly. Increasing leafy vegetables intake may help decrease the CRC risk attributed to interaction of smoking, drinking and relative polymorphisms; it suggests that the diet protective factor can help reduce CRC risks caused by risk factors.In whole, to keep an active spirit status and avoid expose to malignant environment factors such as smoking and alcohol drinking can help decrease CRC incidence; There is not enough evidence to confirm dietary risk factors but which was proved to be dietaryprotective factors, also further supported by the present study, are some vitamins, dietary fibre and leafy vegetables. On consideration of balance diets, if protective foods intake is sufficient, meats should encourage to intake at some extent since its major contribution to a range of important nutrients; Colorectal neoplasia attribute to different environment or dietary factors maybe decided by some special genetic status and by the extent that environment or dietary factors break the balance of metabolism, growth and differentiation maintained.