Given the high rates of colorectal cancer and the potential chemopreventive properties of folate or folic acid, it is crucial to demonstrate in a randomized setting that folic acid supplementation reduces the occurrence of colorectal neoplasia. We thus propose to continue to examine the hypothesis that folic acid supplementation of 1,000 micrograms daily will reduce the recurrence rate of colorectal adenomas, precursors of cancers using a randomized, placebo-controlled intervention trial. This study has been successfully initiated and has been ongoing since 1996 among 750 individuals within two ongoing cohort studies, the Health Professionals Follow-Up Study and the Nurses' Health Study. As planned, we will examine whether any influence of folate is modified by various factors, including baseline folate and vitamin B12 levels, aspirin use, family history of colorectal cancer, and intakes of alcohol and methionine. For this submission, we now propose extending follow-up from three to five years because of recent evidence of a long induction period between folate intake and colorectal cancer, and because recent fortification of food products with folic acid may reduce the contrast of folate status between intervention and placebo groups. We further propose to measure additional folate- related factors (plasma homocysteine, methylene-tetrahydrofolate reductase (MTHFR) genotype) and insulin-like growth factor (IGF) parameters (insulin-like growth factor-1 and insulin-like growth factor binding protein-3), which we have found to be the strongest cluster of etiologic factors for colorectal carcinogenesis in our cohorts. Thus, it is of interest to examine the independent and interacting roles of folate-related and IGF-related factors in adenoma recurrence. Within our existing cohorts, the intervention trial, as well as the proposed additional biomarker and genotype measures, can be conducted at a fraction of the cost of a similarly sized intervention trial of colorectal adenoma recurrence in other typical settings.
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