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Grant Details

Grant Number: 5R01CA078828-03 Interpret this number
Primary Investigator: Reid, Brian
Organization: Fred Hutchinson Cancer Research Center
Project Title: Epidemiology of P16 Inactivation in Barretts Esophagus
Fiscal Year: 2000
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Abstract

DESCRIPTION: Esophageal adenocarcinoma is one of the most rapidly increasing cancers in the United States. Most patients with this cancer present when the tumor is advanced; over 90% will die of their disease. Persons with metaplastic Barrett's esophagus are at high risk of developing this cancer, estimated at 30 - 40 times that of the general population. The neoplastic progression that can be observed in serial esophageal biopsies of persons with Barrett's esophagus involves the development of genetic instability and the accumulation of multiple genetic and cell cycle abnormalities. Inactivation of the p16 tumor suppressor gene occurs relatively early during progression and is detected in approximately 85 percent of patients who develop aneuploidy and cancer. The mechanisms of p16 inactivation involves 9p21 LOH of one allele and either mutation or promoter hypermethylation of the other p16 allele. The Specific Aims of this project are to: 1) determine the prevalence of p16 abnormalities, including p16 mutation, p16 promoter hypermethylation and 9p21 LOH at each stage of histologic progression in patients with Barrett's esophagus; and 2) investigate the association of each abnormality with specific environmental exposures or host factors that are believed to increase risk for esophageal adenocarcinoma. These will include age, gender, tobacco use, alcohol use, body mass index, diet, serum micronutrient levels and use of various medications. An existing cohort of patients who represent all stages of disease and for whom interviews, anthropometry, serum, and biopsies are available will be used for these investigations. DNA content and Ki67/DNA content multiparameter flow cytometry will be used to analyze and to purify cell populations from endoscopic biopsies. The flow-purified samples will then be used to detect p16 mutations, p16 promoter hypermethylation and 9p21 LOH. LOH will be determined by automated genotyping using fluoresce-labeled polymorphic markers within and flanking the p16 locus on 9p21. Mutations in p16 will be detected using PCR template and fluorescent automated sequencing. Promoter hypermethylation will be assayed using methylation-specific PCR and whole genome amplification according to our published protocols. Statistical approaches will include contingency table analysis, logistic regression and generalized linear mixed models. These results will lead to a better understanding of the relationships between etiologic factors and molecular mechanisms for inactivating a human tumor suppressor gene in a highly fatal cancer in vivo.

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Publications

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