6th ESACP Congress, Heidelberg, April 7-11, 1999

A016
GENOMIC INSTABILITY IN GASTROINTESTINAL MODELS OF NEOPLASTIC PROGRESSION
Rabinovitch PS

Dept. of Pathology, University of Washington, Seattle, Washington, USA.

The gastrointestinal tract offers unusual opportunities for the study of early genetic alterations leading to neoplasia. In both Ulcerative Colitis (UC) and Barrett's esophagus we have studied endoscopic biopsies from patients who are at high risk of progression to cancer. In UC flow cytometry was useful to document that DNA aneuploidy, an indicator of genomic instability and clonal expansion, precedes and surrounds regions of dysplasia in the colon. Comparative genomic hybridization (CGH) showed the presence of even larger regions of chromosomal instability in DNA diploid tissue. Fluorescence in situ hybridization (FISH) is the most sensitive of all, and shows that chromosomal instability (CIN) is present throughout the colon of patients that have progressed to focal dysplasia or cancer, but is not present in non-progressors. CIN is not always clonal and involves some chromosomes more than others. One intriguing hypothesis is that CIN in UC is related to shortened telomeres. In Barrett's esophagus flow cytometry has also shown genomic instability and clonal expansion. Sorted epithelial cells from patients with Barrett's esophagus followed prospectively have been used to characterize the sequence and patterns of loss of heterozygosity during neoplastic evolution.