Objective:

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.

Sources:

• The Journal of Molecular Diagnostics