) The incidence of esophageal adenocarcinoma (EA), a rapidly fatal cancer with 5-year survival of less than 10 percent, has risen more then 350 percent over the past 20 years. Neoplastic progression in Barrett's esophagus (BE), the precursor to EA, is characterized by progressive genetic instability, including mutations (p53, p16), promoter hypermethylation (p16), aneuploidy and chromosomal instability (LOH, deletions and amplifications). Barrett's esophagus is an excellent model of human neoplastic progression because endoscopic surveillance is recommended, permitting serial samples to be evaluated over time in the same patient. Shortened telomeres, p53 and p16 inactivation occur before EA. We hypothesize that telomere shortening causes chromosomal instability in BE as has been proposed in model systems. However, relationships among p16/p53 inactivation, reactivation of telomerase, and chromosomal instability during human neoplastic progression are largely unknown. In this proposal, I will investigate the hypothesis that telomere shortening, abrogation of p16 and p53 function and telomerase reactivation interact to mediate chromosomal instability in BE. We propose to measure telomerase activity in BE samples in 325 patients from the Seattle Barrett's Esophagus Cohort, an extremely well characterized cohort for whom p53 and p16 status and flow cytometric data are already known. We will use clonal ordering to determine relationships among p53 inactivation, p16 inactivation, telomerase reactivation and the development of chromosomal instability, using alterations on chromosome 18 as a model of instability. Chromosome 18 is an appropriate model because it is frequently (75 percent of cases) altered in EA (LOH events, amplifications and deletions) and these alterations are selected before the development of cancer. The methods used in these analyses will include TRAP assays to measure telomerase activity and microsatellite LOH and microarray comparative genomic hybridization (CGH) to assess chromosomal instability. The results from these analyses will be of interest to both clinical and basic researchers in studying EA and other cancers.
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