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. 2017 Jun 1;8(9):1517-1524.
doi: 10.7150/jca.17878. eCollection 2017.

Gene Signal Distribution and HER2 Amplification in Gastroesophageal Cancer

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Free PMC article

Gene Signal Distribution and HER2 Amplification in Gastroesophageal Cancer

Jan Trøst Jørgensen et al. J Cancer. .
Free PMC article

Abstract

Background: HER2 serves as an important therapeutic target in gastroesophageal cancer. Differences in HER2 gene signal distribution patterns can be observed at the tissue level, but how it influences the HER2 amplification status has not been studied so far. Here, we investigated the link between HER2 amplification and the different types of gene signal distribution. Methods: Tumor samples from 140 patients with gastroesophageal adenocarcinoma where analyzed using the HER2 IQFISH pharmDx™ assay. Specimens covered non-amplified and amplified cases with a preselected high proportion of HER2 amplified cases. Based on the HER2/CEN-17 ratio, specimens were categorized into amplified or non-amplified. The signal distribution patterns were divided into homogeneous, heterogeneous focal or heterogeneous mosaic. The study was conducted based on anonymized specimens with limited access to clinicopathological data. Results: Among the 140 analyzed specimens 83 had a heterogeneous HER2 signal distribution, with 62 being focal and 21 of the mosaic type. The remaining 57 specimens had a homogeneous signal distribution. HER2 amplification was observed in 63 of the 140 specimens, and nearly all (93.7%) were found among specimens with a heterogeneous focal signal distribution (p<0.0001). The mean HER2/CEN-17 ratio for the focal heterogeneous group was 8.75 (CI95%: 6.87 - 10.63), compared to 1.53 (CI95%: 1.45 - 1.61) and 1.70 (CI95%: 1.22 - 2.18) for the heterogeneous mosaic and homogeneous groups, respectively, (p<0.0001). Conclusions: A clear relationship between HER2 amplification and the focal heterogeneous signal distribution was demonstrated in tumor specimens from patients with gastroesophageal cancer. Furthermore, we raise the hypothesis that the signal distribution patterns observed with FISH might be related to different subpopulations of HER2 positive tumor cells.

Keywords: FISH; HER2; companion diagnostics.; gastroesophageal cancer; signal distribution; tumor heterogeneity.

Conflict of interest statement

Conflict of Interest: Jan Trøst Jørgensen has worked as a consultant for Agilent Technologies and Euro Diagnostica, and has given lectures at meetings sponsored by AstraZeneca, Merck Sharp & Dohme, and Roche. Karsten Bork Nielsen, Gitte Kjærsgaard, Anna Jepsen, and Jens Mollerup are employees of Agilent Technologies.

Figures

Figure 1
Figure 1
Images and schematic illustrations exemplify the different signal distribution patterns identified in gastroesophageal cancer specimens analyzed with HER2 IQFISH pharmDx™. A) HER2 non-amplified tumor cells. B) HER2 amplified tumor cells with homogeneous signal distribution. C) HER2 amplified tumor cells with heterogeneous focal signal distribution with grouped amplified tumor cells surrounded by non-amplified tumor cells. D) Amplified tumor cells with a heterogeneous mosaic signal distribution pattern where the HER2 amplified and non-amplified tumors cells are interspersed. The red dots indicate HER2 signals and green dots indicate CEN-17 signals. Amplified cells are indicated in dark blue in the schematic and non-amplified are light blue. Images are generated at 400x.
Figure 2
Figure 2
Plot of HER2/CEN-17 ratios (N=140) determined by HER2 IQFISH pharmDx™ staining of the gastric cancer specimens by signal distribution group. All specimens are illustrated in A) and in B) specimens up to a HER2/CEN-17 ratio of 4.0 are plotted. Blue data points indicate non-amplified HER2 status and red data points indicate amplified HER2 status. Random jittering by SAS JMP was included to better visualize overlying or nearby data points.

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