[Oncogene amplification and genetic heterogeneity in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus].
OBJECTIVE
Information about numerical genomic alterations in the tumorigenesis of Barrett's adenocarcinoma (BCA) is still limited. In order to search for gene amplification and ploidy status, a series of locus-specific DNA probes and associated centromere probes was analysed in the metaplasia-dysplasia-adenocarcinoma-sequence.


METHODS
Fluorescence in situ hybridisation (FISH) was performed on paraffin sections with locus-specific DNA probes for D7S486, c-myc, cyclin D1, Her-2/neu, 20q13.2 and associated chromosomes 7, 8, 11, 17 and 20. Corresponding areas of intestinal metaplasia (IM, n = 5), low grade dysplasia (LGD, n = 9), high grade dysplasia (HGD, n = 15) and BCA (n = 16) were analysed.


RESULTS
Gene amplification of c-myc, Cyclin D1, Her-2/neu and 20q13.2 was observed in 15-35% of BCA. Coincident amplification of genes was also present. Polysomies for all investigated centromere probes were highly prevalent (up to 85%). Gene amplification was also demonstrated in HGD lesions. Polysomies were observed in HGD in high frequency (up to 80%). Extensive genetic heterogeneity was observed in both, BCA and HGD displaying different levels of amplification. None of the samples with LGD showed a locus-specific amplification, but polysomies for all investigated chromosomes were present in 18-48% of LGD. No changes were detected in BCA associated IM and squamous epithelium.


CONCLUSIONS
Our data indicate that oncogene amplification of c-myc, cyclin D1, Her-2/neu, and 20q13.2 occurring in BCA and less frequently in HGD is a late event in the tumorigenesis. Polysomies of chromosomes 7, 8, 11, 17 and 20, which were highly prevalent in BCA and HGD occur already at the stage of LGD. This may be a result of an early polyploidization, preceding the later genetic events, such as gene amplification in HGD and BCA. The detection of shared numerical genomic changes and the detected extensive genetic heterogeneity in the metaplasia-dysplasia-carcinoma-sequence in Barrett's esophagus supports the hypothesis of a process of multiclonal expansion underlying this progression.
Walch
A
A
Technische Universität München, Institute of Pathology, Munich, Germany.
Bink
K
K
Hutzler
P
P
Zitzelsberger
H
H
Braselmann
H
H
Aubele
M
M
Höfler
H
H
Werner
M
M
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D005784:Gene Amplification; D006801:Humans; D008679:Metaplasia / Q000235:genetics; D009857:Oncogenes