Topoisomerase IIα gene amplification in gastric carcinomas:: correlation with the HER2 gene.: An immunohistochemical, immunoblotting, and multicolor fluorescence in situ hybridization study

Topoisomerase II alpha (topoII alpha) is an enzyme required for DNA replication and a molecular target for drugs called anthracyclines. The topoII alpha gene (TOP2A) is located close to the HER-2/neu oncogene (HER2). We assessed gastric cancers to (1) clarify the relationship between gene amplification and protein overexpression of topoII alpha and HER2; (2) evaluate the correlation between gene amplification and protein overexpression of topoII alpha; and (3) examine the relationship between the results of immunohistochemistry and Western blot analysis for topoII alpha. In a combined analysis of immumohistochemistry and fluorescence in situ hybridization on 552 formalin-fixed and paraffin-embedded gastric cancer tissues, 3 8 cases were found to have HER2 amplification. Further examination by fluorescence in situ hybridization revealed amplification of TOP2A in 13 of the 38 cases. No aberrations in the TOP2A gene were observed in cases without HER2 overexpression, except for one containing a gene deletion. The TopoII alpha protein-labeling index was not correlated with TOP2A amplification. Fluorescence in situ hybridization was performed on nuclear imprint specimens obtained from 9 cases using simultaneous probes for TOP2A, HER2, and centromere 17. Of these 9 cases, 3 displayed coamplification of TOP2A and HER2, and only I of the 3 cases revealed a high expression of topoII alpha in Western, blot. Although patients having gastric adenocarcinoma with TOP2A amplification could be considered suitable for clinical trials, information involving anthracycline therapy is not firmly understood in regards to the status of TOP2A amplification or protein overexpression. Therefore, results of the current study will provide further insight for the clinical application of anthracycline in gastric cancers. (c) 2006 Elsevier Inc. All rights reserved.