HER-2/neu Gene Amplification and Aneuploidy of Chromosome 17 in Pancreatic Ductal Adenocarcinoma
Abstracts
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Background: HER-2/neu is an important oncogene and the gene product is currently tested as therapeutic target in selected adenocarcinomas. The knowledge of Her-2 gene amplification in pancreatic duct cancers is very limited. Fluorescence in Situ Hybridisation does not meet the requirements for the complex morphology of this aggressive tumor. Therefore we have performed chromogenic in situ hybridisation (CISH) on formalin fixed, paraffin embedded tissue specimens, providing an excellent morphology. In this study we evaluate the HER-2/neu and chromosome 17 status in patients with operable adenocarcinomas of the pancreatic duct. Materials and Methods: So far, we have performed CISH on 30 pancreatic duct cancers (pT1-3,pN0-1,pM0) using an a-satellite probe for chromosome 17 and a probe for the HER-2/neu locus, respectively. The probes were detected with mouse anti-digoxigenin, biotin-conjugated goat anti-mouse, peroxidase-conjugated streptavidin and metal-enhanced diaminobenzidine, and the gene copies could be distinguished with a x40 objective in hematoxylin-stained tissue sections. CISH signals were enumerated in 200 intact interphase nuclei. A HER-2/neu / chromosome 17 ratio greater than 2.0 was considered as HER-2/neu gene amplification. Results: All tumors showed heterogeneity with regard to chromosome 17 and HER-2/neu copy number. Eighty per cent of the investigated tumors showed aneuploidy of chromosome 17 (3-5 copies/cell). In 10% we detected a HER-2/neu gene amplification (HER-2/neu / chromosome 17 ratio >2.0). However, if less than 200 nuclei were enumerated, clusters of tumor cells with high level HER-2/neu gene amplification were detected in 40% of the pancreatic cancers. Discussion: Tumor cell heterogeneity and aneuploidy of chromosome 17 was frequently found in the studied pancreatic cancers. If 200 nuclei were counted, the rate of patients with HER-2/neu amplifications was low (10%). But a significant number of patients (40%) showed tumor cell foci with high level HER-2/neu gene amplifications within the tumors. To clarify the significance of this finding, we will present prospective clinical data correlated to our results. Selected patients with HER-2/neu gene amplification might be suitable candidates for adjuvant anti-HER-2/neu strategies. |
