||5R01CA063718-05 Interpret this number
||Johns Hopkins University
||Diet and Genetic Alterations in Colorectal Neoplasia
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
Phenotypic and molecular characteristics of hyperplastic polyposis.
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