Colorectal cancer and diet in Scotland
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Introduction Colorectal cancer is a cancer that forms in the tissues of the colon and/ or rectum and more than 95% of colorectal cancers are adenocarcinomas. It is the third most common cancer in incidence and mortality rates, accounting for 9% of all cancer cases and for 8% of all cancer related deaths (2002). The established risk factors of colorectal cancer include personal or family history of previous colorectal cancer or adenomatous polyps, chronic bowel inflammatory disease and presence of any of the hereditary syndromes. In addition, due to the fact that the majority of colorectal cancer cases (approximately 90%) occur after the age of 50, advanced age is also considered as a risk factor. Finally, evidence for significant associations between colorectal cancer and other risk factors, including diet, body weight, physical activity, smoking, alcohol intake, NSAIDs intake and HRT in post-menopausal women, is promising and increasing. Aims and objectives The main aims of this project were: 1) to investigate the associations between colorectal cancer and specific nutrients, including flavonoids, fatty acids, folate, vitamin B2, vitamin B6, vitamin B12, alcohol, vitamin D and calcium (prior hypotheses 1-4) and 2) to conduct an overall as well as forward and backward stepwise regression analyses of demographic, lifestyle and dietary risk factors. Methods The analysis of this thesis was based on a population-based case-control study of colorectal cancer (Scottish Colorectal Cancer Study; SOCCS). In total 3,417 colorectal cancer cases and 3,396 controls were recruited in the study. Dietary and lifestyle data were collected by two questionnaires (Lifestyle & Cancer and Food Frequency Questionnaire) and were available for 2,061 cases and 2,776 controls. For the analysis of the first two hypotheses (flavonoids and fatty acids) a matched dataset of 1,489 casecontrol pairs was used and conditional logistic regression models were applied, whereas for the analysis of the last two hypotheses (folate, vitamin B2, vitamin B6, vitamin B12, alcohol, vitamin D and calcium) an unmatched dataset including 2,061 cases and 2,776 v controls was used and unconditional logistic regression models were applied. For the overall and stepwise regression analyses the unmatched dataset was used (2,061 cases and 2,776 controls). Forward and backward stepwise regression was applied on three different sets of variables and the stability of the resultant models was checked in 100 bootstrap samples. Results Regarding the first two hypotheses, statistically significant odds ratios (ORs) (matched on sex, age and health board are and adjusted for family history of cancer, BMI, physical activity, smoking, and intakes of total energy, fibre, alcohol and NSAIDs) for highest versus lowest intakes (quartiles) were observed for flavonols OR (95% CI), p-value for trend: 0.78 (0.60, 0.99), 0.08) and for the individual flavonoid compounds quercetin and catechin (OR (95% CI), p-value for trend: 0.77 (0.60, 0.99), 0.04; 0.75 (0.58-0.97), 0.02; respectively); for the 3PUFAs fatty acids (OR (95% CI), p-value for trend: 0.75 (0.59, 0.97), 0.01) and for the individual fatty acids stearic acid, EPA and DHA (OR (95% CI), p-value for trend: 1.46 (1.11, 1.91), 0.01; 0.74 (0.58, 0.95), 0.02; 0.74 (0.58, 0.95), 0.02; respectively). Regarding the last two hypotheses, statistically significant odds ratios (ORs) (adjusted for age, sex, deprivation score, family history of cancer, BMI, physical activity, smoking, and intakes of total energy, fibre, alcohol and NSAIDs) for highest versus lowest intakes (quartiles) were observed for vitamin B6, vitamin B12 and alcohol (OR (95% CI), p-value for trend: 0.86 (0.72, 1.03), 0.08; 0.80 (0.67, 0.97), 0.05; 0.83 (0.68, 1.00), 0.03); and for vitamin D (OR (95% CI), p-value for trend: 0.83 (0.69, 0.99), 0.03). Regarding the second aim of the project, several risk factors were found to be significantly associated with colorectal cancer in the overall analysis including demographic and lifestyle factors (family history of cancer, NSAIDs intake, dietary energy intake, HRT intake and physical activity), food group variables (vegetables, eggs, sweets, fruit/ vegetable juice, oily fish, coffee, fruit, savoury foods and white fish) and nutrient variables (tMUFAs, 3PUFAs, SFAs, tFAs, MUFAs, quercetin, catechin, phytoestrogen, cholesterol, fibre, protein, starch, magnesium, potassium, manganese, copper, iron, zinc, phosphorus, selenium, niacin, vitamin B6, carotenes, vitamin C, vi vitamin A, potential niacin, biotin, folate, pantothenic acid, vitamin D, vitamin B1 and vitamin B12). In addition, the variables that were selected to be included in 100% of the models after applying forward and backward stepwise regression analyses were family history, NSAIDs, sweets and fruit/ vegetable juice. Finally according to the findings from the bootstrap analysis, the variables that were selected to be included in models for the majority of the bootstrap samples (more than 90%) were family history, NSAIDs, dietary energy, eggs, sweets, fruit/ vegetable juice and white fish. Discussion The particular dietary factors that were found to be inversely associated with colorectal cancer after applying several multivariable logistic regression models were: flavonols, quercetin, catechin, 3PUFAs, EPA, DHA, vitamin B6, vitamin B12 and vitamin D. In addition, high intakes of stearic acid were found to be positively associated with colorectal cancer. In contrast, high intakes of dietary and total folate were associated with a decreased colorectal cancer risk in the energy-adjusted model, but this inverse association was attenuated after further adjustment for several confounding factors including fibre. Regarding alcohol intake, when it was divided into quartiles, high alcohol consumption was associated with a statistically significant and dose-dependent decreased colorectal cancer risk. However, when alcohol intake was divided in categories an increased colorectal cancer risk for intakes of higher than 60 g/day was observed. Intakes of 3PUFAs, vitamin D and vitamin B12 were highly correlated due to having the same food source (oily fish) and therefore it is difficult to draw specific conclusions regarding which nutrient is truly associated with colorectal cancer and which not. Finally, it was observed that for calcium intakes to be inversely associated with colorectal cancer, a dosage of 1500mg/day or higher was necessary. The majority of these results are in accordance with results of previous epidemiological and laboratory studies; however their confirmation in further large-scale studies is required. Results from the overall and stepwise regression analysis supported previous findings of an increased colorectal cancer risk due to a high or moderate family history risk. In addition, high intakes of dietary energy were found to be positively associated with increased colorectal cancer risk in the overall analysis and in addition dietary energy was vii selected to be included in the majority of the stepwise regression models. On the other hand, regular intake of NSAIDs was found to be inversely associated with colorectal cancer risk in the overall analysis and in the majority of the stepwise regression models. Finally, the overall and stepwise regression analyses generated a few new hypotheses suggesting that low intakes of fruit/ vegetable juice, eggs, white fish and sweets (a combined variable of high-fat and high-sugar foods) and high intakes of coffee and magnesium were associated with a decreased colorectal cancer. These findings, though interesting and important for generation of new hypotheses, need further investigation (as prior hypotheses) in large-scale observational studies.