Study suggests RNA analysis identifies mutations missed by DNA-only approaches, improving diagnostic accuracy for targeted treatment.
New research indicates that RNA-based testing can improve the detection and interpretation of genomic alterations leading to MET exon 14 skipping in lung cancer patients. The findings, published in The Journal of Molecular Diagnostics, suggest that these biomarkers are often missed by DNA-only approaches, which may impact patient eligibility for MET-targeted therapies.
The mutations leading to MET exon 14 skipping occur in 3% to 4% of non-small cell lung cancer (NSCLC) patients. These alterations are heterogeneous and occur across a broad splice-site region, creating analytical challenges for both DNA- and RNA-based next-generation sequencing (NGS) assays.
Identifying Molecular Complexity
In a study of a large real-world cohort of NSCLC patients, researchers identified 171 distinct mutations affecting the MET exon 14 splice region. RNA analysis confirmed exon 14 skipping for more than 100 different alteration types.
“Although MET exon 14 is a well-established predictive biomarker, our findings highlight a level of molecular complexity that is often underappreciated in routine diagnostic practice,” says lead investigator Carina Heydt, PhD, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Institute of Pathology, in a release.
The research demonstrated that certain clinically relevant events, such as large genomic deletions and synonymous variants affecting splicing, may be missed or incorrectly interpreted by DNA-based testing alone. According to the study, incorporating RNA-based confirmation can improve sensitivity and specificity for identifying true exon-skipping events.
Laboratory Performance and Quality Assessment
The researchers also evaluated laboratory performance through multinational external quality assessment (EQA) schemes using both tissue and liquid biopsy samples. Tissue-based testing showed a 98% success rate, indicating that laboratories can achieve reliable detection using validated methodologies.
However, liquid biopsy testing proved more difficult. While performance improved from a 37.5% success rate in 2022 to a 63% success rate in 2024, the study notes that detecting MET exon 14 alterations in circulating tumor DNA remains technically demanding.
Accurate detection is essential because it determines which patients are eligible for MET-targeted therapies.
“Our study provides evidence supporting the complementary role of RNA-based testing in the assessment of MET exon 14 alterations and highlights the value of EQA programs in monitoring assay performance, identifying analytical limitations, promoting harmonization of testing strategies, and ensuring accurate and reproducible results for patient selection for MET-targeted therapies,” says Heydt in a release.
