My overall research aim is to understand the effects of diet on colorectal adenomas, known precursors of colorectal cancer. We recently completed the Polyp Prevention Trial (PPT) a large-scale multi-center dietary intervention clinical trial to examine the effect of a low-fat, high-fiber, high-fruit and vegetable intervention on recurrence of adenomatous polyps of the colorectum. There was no effect of a comprehensive dietary intervention on the recurrence of colorectal adenomas during the four years of the trial, however, since diet may affect early molecular and cellular events in colorectal neoplasia, a statistically significant intervention effect may emerge after the four years of the trial. Data analysis is just beginning on the PPT Continued Follow-up Study, which has collected 8 year post-baseline follow-up data on 1357 participants. I am also conducting a number of sub-studies in the PPT to better understand the epidemiology of colorectal adenomas. One dietary finding in the PPT cohort is that legumes intake was significantly associated with both adenoma recurrence and advanced adenoma recurrence. The odds ratio (OR) comparing the lowest to the highest quartiles for advanced adenomas was OR=0.30, 95% CI=0.15-0.60, and there was a significant trend. Legumes are a rich source of fermentable dietary fibers which are precursors of luminal butyrate. The anti-inflammatory actions of butyrate are supported by both clinical and animal studies, and the anti-neoplastic effects of butyrate have been demonstrated in various in vitro systems. In addition, legumes have a low glycemic index (GI). A high glycemic index diet is associated with both type 2 diabetes (DM) and colon cancer risk and a number of epidemiologic studies have provided convincing evidence for an association between DM, insulin resistance (IR) and colon cancer. Additionally, both insulin resistance and colorectal cancer are increasingly recognized as chronic, low-level, inflammatory states. The Colon Cancer Prevention Group is conducting a number of studies to further understand the role inflammation and insulin resistance in colon cancer and the role of diet in mediating these risks. A controlled feeding study in men with a history of adenomas is being conducted to understand whether legumes increases fecal butyrate, decreases circulating inflammatory cytokines and acute phase proteins, and alters gene expression in fecal colonocytes. The effects of diet on gene expression in exfoliated cells should provide insights on dietary induced changes in colonic epithelial. We recently initiated study on the effects of legumes and legume components on the inhibition of colon carcinogenesis in azoxymethane (AOM) induced colon cancers in male and female C57BL/6J Ob/Ob mice. This project will help us understand whether fiber or other phytochemical components of legumes are responsible for the reduction in adenoma recurrence, and the mechanisms relating obesity, insulin resistance and colon cancer. While data suggest that inflammatory mediators are elevated in patients with colon cancer, and may in fact, be elevated in subjects with adenomatous polyps, it is unclear at this time if the inflammatory cytokines reported are produced by the transformed epithelial cells and/or immune cells in the polyp or if a state of chronic inflammation induced by obesity and or insulin resistance increases the likelihood of polyp formation and/or reoccurrence. Current studies are underway to address these issues. To investigate the inter-individual variation in the diet and adenoma associations, interactions between dietary factors and single nucleotide polymorphisms SNPs in specific genes in the PPT was undertaken. The initial analysis will focus on three areas: 1. Genes related to obesity, BMI, body fat distribution, hyperinsulinemia, and inflammation, 2. Genes related to behavior, i.e. making and maintaining dietary changes have a genetic component, 3. genes related to DNA repair. Knowing what dietary factors are associated with cancer risk reduction is important, but not sufficient for cancer prevention. Research clearly suggests that dietary changes are difficult both to initiate and to maintain. Therefore, we are trying to understand factors associated with making dietary change in the PPT intervention by examining a variety of baseline and trial behaviors variables associated with success in achieving the PPT fat, fiber, and fruit and vegetables goals
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