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. 2017 Jan;96(2):e5582.
doi: 10.1097/MD.0000000000005582.

Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer

Jim-Ray Chen  1 , Hui-Ping Chien, Kuo-Su Chen, Cheng-Cheng Hwang, Huang-Yang Chen, Kun-Yan Yeh, Tsan-Yu Hsieh, Liang-Che Chang, Yuan-Chun Hsu, Ren-Jie Lu, Chung-Ching Hua
Affiliations

Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer

Jim-Ray Chen et al. Medicine (Baltimore). 2017 Jan.

Abstract

Background: The prognostic relevance of topoisomerase II alpha (TOP2A) copy number change remains not well established. This study is aimed to investigate the frequency and pattern of TOP2A aberrations; to correlate TOP2A alterations with human epidermal growth factor receptor 2 (HER2) status and clinicopathological parameters, and further to explore prognostic value of TOP2A and HER2 status in breast cancer in Taiwan.

Methods: We analyzed tissue samples from 311 invasive carcinomas in tissue microarrays for TOP2A and HER2 status by fluorescent in situ hybridization.

Results: TOP2A copy number change is an infrequent genetic event (9.8% amplification and 2.7% deletion) and is present in both HER2-amplified and nonamplified tumors. TOP2A amplification is statistically associated with age >50 at diagnosis (P = 0.016) and HER2 amplification (P < 0.001). HER2 amplification, but not TOP2A amplification, is a predictor of unfavorable prognosis (P = 0.002). Univariate and multivariate analysis showed that higher histologic grading, positive nodal involvement, and HER2 positivity were associated with poorer overall survival. Cytogenetically, double minutes-type amplification is the predominant pattern for both genes (HER2: 64% and TOP2A: 93.1%). Homogeneous staining region-type signals of both genes are resistant to RNase digestion, supporting that these were not nuclear accumulation of mRNA transcripts.

Conclusion: Our results demonstrate the prognostic value of tumor grading, nodal involvement, and HER2 status in Taiwanese breast cancer. TOP2A aberrations are an infrequent event independent of HER2 status, and TOP2A amplification carries no prognostic value. The predictive value of TOP2A aberrations in patients of breast cancer taking athracycline-containing treatment in Taiwan remains to be determined in prospectively well-designed clinical trials.

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Conflict of interest statement

The authors have declared that no conflicting interests exist.

Figures

Figure 1
Figure 1
Representative micrographs of TOP2A-immunostained images analyzed by ImmunoRatio. The upper panel (A, B, and C) showed 3 different fields of TOP2A-immunostained images taken from a core of tissue microarray. Corresponding images analyzed using ImmunoRatio were shown in the lower panel (D, E, and F). (x200 original magnification).
Figure 2
Figure 2
Representative micrographs of HER2 FISH. (A) A tumor with DM-type amplification displayed rather homogeneous population of cells having multiple individual HER2 signals (orange). (B) Tumor with HSR-type showed characteristic clustered HER2 signals (orange) in most tumor cells. (C) Clustered HER2 signals (orange) remained unchanged following RNase A pretreatment. (1000x magnification).
Figure 3
Figure 3
Representative micrographs of TOP2A FISH. (A) One tumor with DM-type amplification typically displayed multiple individual TOP2A signals (orange). (B) One tumor with HSR-type amplification showed clustered TOP2A signals, resistant to RNase pre-treatment. (C) A TOP2A-deleted tumor demonstrated absence or 1 copy of TOP2A signals and 2–4 CEP 17 signals (green). (1000x magnification).
Figure 4
Figure 4
HER2/CEP17 ratio plotted against TOP2A/CEP17 ratio in 296 tumors with paired ratios.
Figure 5
Figure 5
Kaplan–Meier survival curve. (A) HER2 status (P = 0.002), (B) TOP2A status (P = 0.867), (C) TOP2A index (P = 0.267), and (D) HER2 amplification with or without simultaneous amplification of TOP2A (P = 0.258).
See this image and copyright information in PMC

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