Detection of MET amplification in gastroesophageal tumor specimens using IQFISH

Jan Trøst Jørgensen; Karsten Bork Nielsen; Jens Mollerup; Anna Jepsen; Ning Go

doi:10.21037/atm.2017.09.07

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH

Ann Transl Med. 2017 Dec;5(23):458. doi: 10.21037/atm.2017.09.07.

Authors

Jan Trøst Jørgensen¹, Karsten Bork Nielsen², Jens Mollerup², Anna Jepsen², Ning Go³

Affiliations

¹ Department of Companion Diagnostic Research, Dx-Rx Institute, Fredensborg, Denmark.
² R&D, Diagnostics and Genomics Group, Agilent Technologies Denmark Aps, Glostrup, Denmark.
³ Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.

Abstract

Background: The gene mesenchymal epithelial transition factor (MET) is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer.

Methods: Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET/CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET/CEN-7 ratio ≥2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated.

Results: The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non-amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2-13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET/CEN-7 ratio (2.35 versus 1.04; P<0.0001).

Conclusions: The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern.

Keywords: Mesenchymal epithelial transition factor (MET); amplification; fluorescence in situ hybridization (FISH); gastroesophageal cancer; reproducibility; signal distribution.