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Updated: Jan 1, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer
M A Pruis1, W R R Geurts-Giele2, Thüsen J H von der2
1Department of Pulmonary Diseases, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Objectives:
The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3 %-5.7 % of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63 % of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms.
Material And Methods:
Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del.
Results:
In silico analysis showed that our NGS panel is able to detect 96 % of reported METex14 alterations. METex14del was found in 2 % of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015 - Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced non-squamous NSCLC, they were predominantly elderly (76.5 years [53-90]), male (25/36) and (ex)-smokers (23/36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib.
Conclusions:
This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.
Insights
A new DNA-based test reliably detects MET exon 14 skipping mutations in non-small-cell lung cancer. Patients with METex14del responded well to targeted therapy, highlighting the need for routine diagnostic testing.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- MET exon 14 skipping mutations (METex14del) are oncogenic drivers in 1.3%-5.7% of non-small-cell lung cancer (NSCLC).
- RNA-based analysis is optimal for METex14del detection, but RNA acquisition is often problematic.
- Existing DNA-based panels detect only up to 63% of METex14del alterations.
Purpose of the Study:
- To describe an optimized DNA-based diagnostic test for METex14del in NSCLC.
- To analyze clinical features and treatment outcomes of patients with METex14del.
- To investigate resistance mechanisms to cMET-targeted therapy.
Main Methods:
- A custom-designed DNA-based targeted amplicon sequencing (NGS) panel was developed for METex14del detection.
- Routinely processed diagnostic pathology specimens from non-squamous NSCLC patients were analyzed.
- Histopathological characteristics and clinical follow-up data were retrospectively collected.
Main Results:
- The NGS panel demonstrated 96% detection rate for reported METex14 alterations.
- METex14del was identified in 2% of NSCLC patients tested, with 46 cases identified between May 2015 and September 2018.
- Patients with advanced NSCLC harboring METex14del showed good response to crizotinib treatment, with 4/5 achieving disease control.
Conclusions:
- Routine DNA-based NGS analysis reliably detects METex14del in NSCLC.
- Targeted therapy demonstrates efficacy in patients with METex14del.
- Routine testing for METex14del in advanced NSCLC is crucial for personalized treatment strategies.
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