Abstract

MET gene alterations are known to be involved in acquired resistance to epidermal growth factor receptor inhibition. MET amplifications present a potential therapeutic target in non-small cell lung cancer. Although next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are conventionally used to assess MET amplifications, there are currently no clinically defined cut-off values for NGS, with FISH still being the gold standard. A collective of 20 formalin-fixed paraffin-embedded lung cancer tissue samples (mean age 64 years) were selected based on increased MET gene copy number (CNV) status or the presence of mutations detected by NGS (GeneReader, QIAGEN) and were further assessed by FISH (MET/CEN7, Zytomed). Of these, 17 tumor samples were MET-amplified and one patient was found to have a MET rearrangement by NGS, while two samples had no MET gene alteration. In contrast to the NGS result, FISH analysis showed only one highly amplified sample and 19 negative samples. The single highly amplified case detected by FISH was also positive by NGS with a fold change (FC) of 3.18 and a mean copy number (CNMV 10−100%) of 20.5. Therefore, for the assessment of MET amplifications using the QIAGEN NGS workflow, we suggest detecting amplified cases with an FC value of ≥ 3.0 and a CNMV 10−100% value of ≥ 20.0 by FISH. In summary, NGS allows for DNA- and RNA-based analysis of specific MET gene amplifications, point mutations or rearrangements.

Highlights

  • The proto-oncogene mesenchymal-epithelial transition (MET) encodes for a receptor tyrosine kinase which is a ubiquitously expressed cell surface receptor consisting of an extracellular alphachain disulfide-bonded to a membrane spanning betachain [1, 2]

  • The cohort consisted of 10 men (50%) and 10 women (50%). 18 (90%) lung carcinomas and two cancers (10%) of unknown primary were included in the study

  • The patient collective was compiled based on the next-generation sequencing (NGS) result, wherein the selection criterion for the samples was the presence of a MET amplification and an overall sufficient sequencing quality, based on the quality parameters specified by the analysis software (QCI-A), to avoid false positive cases

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Summary

Introduction

The proto-oncogene MET encodes for a receptor tyrosine kinase which is a ubiquitously expressed cell surface receptor consisting of an extracellular alphachain disulfide-bonded to a membrane spanning betachain [1, 2]. The activity of MET tyrosine kinase is activated and can lead to effects on cell growth, mortality, survival, invasion and angiogenesis [5,6,7]. Dysregulations in the signaling pathway were first investigated in 1990 as a possible cause of lung cancer [8]. Activation of the MET signaling pathway resulting from MET amplification or splice site alterations in MET exon 14 is associated with lung cancer growth and metastasis [9, 10]. MET amplification correlate with shorter overall survival in non-small cell lung cancer patients and, has prognostic value [11,12,13]

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