Analysis of EGFR, HER2, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients

Zhiyong Liang,Jie Gao,Peng Wang,Jing Zhang,Xuan Zeng,Shafei Wu,Xiaohua Shi,Tonghua Liu

doi:10.1186/1471-2407-8-363

Abstract

BackgroundThe EGFR and HER2 genes are located on chromosomes 7 and 17, respectively. They are therapeutic targets in some tumors. The TOP2A gene, which is located near HER2 on chromosome 17, is the target of many chemotherapeutic agents, and co-amplification of HER2 and TOP2A has been described in several tumor types. Herein, we investigated the gene status of EGFR, HER2, and TOP2A in Chinese gastric carcinoma patients. We determined the rate of polysomy for chromosomes 7 and 17, and we attempted to clarify the relationship between EGFR, HER2, and TOP2A gene copy number and increased expression of their encoded proteins. Furthermore, we tried to address the relationship between alterations in EGFR, HER2, and TOP2A and chromosome polysomy.MethodsOne hundred cases of formalin fixed and paraffin embedded tumor tissues from Chinese gastric carcinoma patients were investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) methods.ResultsForty-two percent of the cases showed EGFR overexpression; 16% showed EGFR FISH positive; 6% showed HER2 overexpression; and 11% showed HER2 gene amplification, including all six HER2 overexpression cases. TOP2A nuclear staining (nuclear index, NI) was determined in all 100 tumors: NI values ranged from 0.5 – 90%. Three percent of the tumors showed TOP2A gene amplification, which were all accompanied by HER2 gene amplification. Nineteen percent of the tumors showed chromosome 7 polysomy, and 16% showed chromosome 17 polysomy. Chromosome 7 polysomy correlated significantly with EGFR FISH-positivity, but was not associated with EGFR overexpression. HER2 overexpression associated significantly with HER2 gene amplification. TOP2A gene amplification was significantly associated with HER2 gene amplification. No relationship was found between alterations in the EGFR, HER2, and TOP2A genes and clinicopathologic variables of gastric carcinoma.ConclusionThe data from our study suggest that chromosome 7 polysomy may be responsible for increased EGFR gene copy number in gastric carcinomas, and that HER2 gene amplification may be the major reason for HER2 protein overexpression. A combined investigation of the gene status of EGFR, HER2, and TOP2A should facilitate the identification of a target therapeutic regimen for gastric carcinoma patients.

Highlights

The epidermal growth factor receptor (EGFR) and HER2 genes are located on chromosomes 7 and 17, respectively
EGFR overexpression was not associated with EGFR fluorescence in situ hybridization (FISH) positivity (p > 0.0026) (Table 1, Figure 1)
HER2 gene amplification correlated significantly with HER2 protein overexpression, whereas EGFR gene amplification and TOP2A gene amplification were not associated with corresponding increases in protein expression; the mechanism remains to be clarified

Summary

Introduction

The EGFR and HER2 genes are located on chromosomes 7 and 17, respectively They are therapeutic targets in some tumors. We investigated the gene status of EGFR, HER2, and TOP2A in Chinese gastric carcinoma patients. We determined the rate of polysomy for chromosomes 7 and 17, and we attempted to clarify the relationship between EGFR, HER2, and TOP2A gene copy number and increased expression of their encoded proteins. Several molecules have been synthesized that inhibit EGFR and HER2 tyrosine kinase domains These tyrosine kinase inhibitors produced significant responses in advanced NSCLC and breast cancer, and some have been used in the treatment of gastric cancer. Investigating the gene status of EGFR and HER2 is crucial to determining those patients who would benefit most from target therapies [6,7,8]

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Discussion

Conclusion