Grant Number:	5R01CA063718-05 Interpret this number
Primary Investigator:	Hamilton, Stanley
Organization:	Johns Hopkins University
Project Title:	Diet and Genetic Alterations in Colorectal Neoplasia
Fiscal Year:	1998

Epidemiologic evidence indicates that environmental factors, especially diet, are related to the risk of colorectal carcinoma. Inherited molecular genetic alterations in the Adenomatous Polyposis Coli (APC) gene and the putative Hereditary Nonpolyposis Colorectal Cancer syndrome (HNPCC) gene as well as somatic alterations in the APC, ras, Deleted in Colorectal Carcinomas (DCC), and p53 genes during the adenoma-carcinoma sequence have been identified. However, the relationships between these molecular genetic events and dietary factors have not been studied. We propose to test two hypotheses: (1) Dietary factors affect the genes involved in progression through the adenoma-carcinoma sequence (ras, DCC and p53). (2) High fiber supplementation reduces the molecular genetic changes in adenomas. To address the first hypothesis, Specific Aim #1 is to characterize the frequency and pattern of genetic alterations in colorectal adenomas in three large patient series and explore the relationships between these genetic alterations and dietary components, especially fiber. We will conduct a cross-sectional study of patients referred for evaluation of colonic polyps in two large medical centers and in gastroenterologists' practices. All patients will complete the HHHQ food frequency questionnaire from which macronutrient and micronutrient intake will be calculated. The removed polyps will be characterized for replication error (RER) phenotype attributed to germline alteration in the HNPCC gene, ras gene mutation, DCC deletion, and p53 mutation. It is expected that a total of approximately 1500 patients will be accrued in this component of the study, of whom 5% are expected to have RER phenotype. The dietary components will be related statistically to the genetic alterations. For the second hypothesis, Specific Aim #2 is to study prospectively the effect of high fiber supplementation on molecular genetic changes in adenomas. We will compare the prevalence of genetic alterations in the recurrent adenomas of patients treated with 20 g/day wheat fiber supplementation or placebo in the ongoing Colon Polyp Prevention Demonstration Study clinical trial of dietary intervention examining the effect of high fiber supplementation on the recurrence rate of adenomas. The results of these studies will be critical in linking current molecular biological understanding of colorectal tumorigenesis with strategies to reduce mortality from colorectal carcinoma via dietary intervention and chemoprevention.





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