Diet and Gastrointestinal Cancer one-carbon metabolism and other aspects

Diet has been hypothesized to play a major role in the etiology of gastrointestinal cancer, but the specific dietary factors involved remain unclear. The aims of this thesis were: to examine the associations of dietary magnesium and vitamin B6 intakes with risk of colorectal cancer in the Swedish Mammography Cohort (SMC); to evaluate the relation between folate intake and risk of pancreatic cancer in the SMC and the Cohort of Swedish Men (COSM); to use metaanalysis to summarize the evidence from published studies of the associations of folate intake and polymorphisms in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), a central enzyme in one-carbon metabolism, with risk of esophageal, gastric, pancreatic, and colorectal cancer; and to perform a meta-analysis of epidemiologic studies of the relationship between processed meat consumption and risk of gastric cancer. The SMC is a prospective cohort study of 61 433 women in central Sweden who were cancer-free and had completed a dietary questionnaire at enrollment between 1987 and 1990. Participants received a second questionnaire in 1997 that included details on diet and other lifestyle factors. The COSM is a prospective cohort study of 45 306 men in central Sweden who were cancer-free and had completed a questionnaire in 1997. Multivariate rate ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. We ascertained 805 incident cases of colorectal cancer in the SMC from baseline through June 30, 2004. Dietary intakes of magnesium and vitamin B6 were statistically significantly inversely associated with the risk of colorectal cancer. The multivariate rate ratios comparing the highest with the lowest quintile of intake were 0.59 (95% CI, 0.40-0.87; Ptrend = 0.006) for magnesium and 0.66 (95% CI, 0.50-0.86; Ptrend = 0.002) for vitamin B6. In the SMC and the COSM, 135 incident cases of pancreatic cancer were diagnosed from 1998 through December 31, 2004. Intake of folate from diet but not from supplements was inversely associated with the risk of pancreatic cancer. The multivariate rate ratio for women and men in the highest category of dietary folate intake (≥350 g/day) compared with those in the lowest category (<200 g/day) was 0.25 (95% CI, 0.11-0.59; Ptrend = 0.002). For the meta-analyses, epidemiologic studies were identified by searching MEDLINE (1966–March 2006) and the reference lists of pertinent articles. Study-specific results were combined using a random-effects model. The summary relative risks (95% CI) for the highest versus the lowest dietary folate intake category were 0.62 (0.53-0.72) for esophageal cancer (7 case-control), 0.90 (0.72-1.13) for gastric cancer (9 case-control, 2 cohorts), 0.49 (0.350.67) for pancreatic cancer (1 case-control, 4 cohorts), and 0.75 (0.66-0.87) for colorectal cancer (6 cohorts). Comparing the MTHFR 677TT genotype with the 677CC genotype, the summary odds ratios (95% CI) were 1.59 (0.98-2.58) for esophageal cancer, 1.90 (1.38-2.60) for gastric cardia cancer, 1.68 (1.29-2.19) for gastric cancer, 2.28 (0.91-5.71) for pancreatic cancer, and 0.84 (0.75-0.95) for colorectal cancer. For colorectal cancer, the summary odds ratio for the MTHFR 1298CC versus the 1298AA genotype was 0.82 (95% CI, 0.65-1.03). Six prospective studies and nine case-control studies were included in the dose-response meta-analysis of processed meat consumption and gastric cancer risk. The summary relative risks for a 30 g/day increment in processed meat consumption were 1.15 (95% CI, 1.04-1.27) in prospective studies and 1.38 (95% CI, 1.19-1.60) in case-control studies. In conclusion, our findings provide support for a role of diet and one-carbon metabolism related gene polymorphisms in the etiology of gastrointestinal cancer. Specifically, our results suggest that increased consumption of foods rich in magnesium, vitamin B6, and folate as well as reduced consumption of processed meat may lower the risk of gastrointestinal cancer. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA 2005;293:86-9 II. Larsson SC, Giovannucci E, Wolk A. Vitamin B6 intake, alcohol consumption, and colorectal cancer: a longitudinal population-based cohort of women. Gastroenterology 2005;128:1830-7 III. Larsson SC, Hakansson N, Giovannucci E, Wolk A. Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. Journal of the National Cancer Institute 2006;98:407-13 IV. Larsson SC, Giovannucci E, Wolk A. Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 2006;131:1271-83 V. Larsson SC, Orsini N, Wolk A. Processed meat consumption and stomach cancer risk: a meta-analysis. Journal of the National Cancer Institute 2006;98:1078-87 LIST OF RELATED PUBLICATIONS