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.
If you are accessing this page during weekend or evening hours, the database may currently be offline for maintenance and should operational within a few hours. Otherwise, we have been notified of this error and will be addressing it immediately.
Please contact us
if this error persists.
We apologize for the inconvenience.
- The DCCPS Team.