To evaluate current testing approaches for detecting MET exon 14 skipping variants in non-small cell lung cancer (NSCLC) and identify limitations in diagnostic accuracy.
Approach:
Study Design: Analysis of 379 NSCLC samples collected between 2016 and 2024 to identify MET exon 14 and splice-site variants.
Testing Methods: Comparison of DNA- and RNA-based next-generation sequencing (NGS) for confirming exon 14 skipping.
Quality Assessment: Examination of the first multinational external quality assessment (EQA) programs for MET exon 14 testing.
Key Findings:
171 distinct MET exon 14 and splice-site variants were identified.
RNA testing confirmed exon 14 skipping in 107 out of 114 variants assessed.
Two large deletions were missed by DNA-based testing but visible in raw data.
57 variants could not be evaluated due to insufficient tissue or RNA quality.
Tissue-based testing had a 98% success rate in EQA, while liquid biopsy testing improved from 38% to 63% pass rates from 2022 to 2024.
Interpretation:
The study highlights the challenges in detecting MET exon 14 alterations.
Limitations:
Insufficient tissue or inadequate RNA quality limited the evaluation of some variants.
False-negative results were common in liquid biopsy testing, particularly for low allele fractions.
Conclusion:
Combining DNA- and RNA-based testing may reduce missed clinically relevant variants.
The assay is indicated to identify patients with advanced melanoma who have BRAF V600E or BRAF V600K variants and may benefit from FDA-approved targeted therapies.
