BARRETTS-ESOPHAGUS - METAPLASTIC CELLS WITH LOSS OF HETEROZYGOSITY ATTHE APC GENE LOCUS ARE CLONAL PRECURSORS TO INVASIVE ADENOCARCINOMA

Adenocarcinoma in Barrett's esophagus is the second most rapidly incre asing cancer in western society, The cause and pathogenesis are unknow n, Although histological studies suggest that there is successive prog ression from metaplasia and dysplasia, with a high risk of subsequent invasive carcinoma, at present there is no direct evidence that metapl astic and dysplastic epithelia are clonal precursors of adenocarcinoma , We selected 12 esophagectomy specimens of Barrett's esophagus patien ts, which showed a spectrum of normal tissue, metaplasia, dysplasia, a nd invasive adenocarcinoma in each individual biopsy, We applied the m icrodissection technique to selectively procure microscopic tissue sam ples from H&E-stained slides for genetic evaluation using polymorphic markers flanking the APC gene locus, Identical APC gene alterations we re found in the dysplastic and adenocarcinoma foci of all informative cases, The same changes were observed even in some metaplastic foci ad jacent to dysplasia, Furthermore, clonality analysis of X-chromosome i nactivation in female cases verified the same X-chromosome inactivatio n pattern in carcinoma, dysplasia, and metaplasia adjacent to dysplasi a, No APC gene alterations were found in the normal epithelium and met aplasia distant from dysplasia, These data show for the first time tha t a tissue field of genotypic changes precedes the histopathological p henotypic changes of carcinoma in Barrett's esophagus syndrome, Our fi ndings, in conjunction with the applied tissue microdissection techniq ue, may help identify genotypic changes in patients with Barrett's eso phagus before phenotypic changes occur, Therefore, genotyping of Barre tt's metaplastic epithelium may supplement the histopathological evalu ation of Barrett's esophagus.