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Updated: Mar 2, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values
Geun Dong Lee1, Seung Eun Lee2, Doo-Yi Oh3
1Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Introduction:
Response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC with mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14) has fueled molecular screening efforts and the search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping.
Methods:
Among 795 East Asian patients who underwent a surgical procedure for NSCLC, we screened 45 patients with quintuple-negative (EGFR-negative/KRAS-negative/anaplastic lymphoma kinase gene [ALK]-negative/ROS1-negative/ret proto-oncogene [RET]-negative) lung adenocarcinomas by using reverse-transcriptase polymerase chain reaction and found 17 patients (37.8%) with METex14 skipping. We also investigated the effect of small interfering RNA (siRNA) targeting skipping junction in cells with METex14 skipping.
Results:
The median age of the 17 patients was 73 years. The acinar subtype was predominant (52.9%), followed by the solid subtype (35.3%). MET immunohistochemistry demonstrated 100% sensitivity and 70.4% specificity. Multivariate analyses showed that patients with METex14 skipping had a higher recurrence rate than those with ALK fusion (versus METex14 skipping) (hazard ratio = 0.283, 95% confidence interval: 0.119-0.670) in stage I to IIIA disease; however, the differences in overall survival were not significant after adjustment for pathologic stage (p = 0.669). Meanwhile, siRNA decreased MET-driven signaling pathways in Hs746T cells, and combined treatment with siRNA and crizotinib inhibited cell proliferation in crizotinib-resistant H596 cells.
Conclusions:
The prevalence of METex14 skipping was quite high in East Asian patients without other driver mutations in lung adenocarcinomas. METex14 skipping was associated with old age, the acinar or solid histologic subtype, and high MET immunohistochemical expression. The prognosis of patients with METex14 skipping was similar to that of patients with major driver mutations. siRNA targeting the junction of METex14 skipping could inhibit MET-driven signaling pathways in cells with METex14 skipping.
Insights
Mesenchymal-epithelial transition (MET) exon 14 skipping (METex14) is prevalent in East Asian lung adenocarcinoma patients lacking other driver mutations. METex14 skipping is linked to older age, specific subtypes, and high MET expression, with a prognosis similar to major driver mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mesenchymal-epithelial transition (MET) inhibitors are crucial for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METex14).
- Refining the clinicopathologic and prognostic implications of METex14 skipping is essential for optimal therapeutic strategies.
Purpose of the Study:
- To determine the prevalence of METex14 skipping in East Asian patients with quintuple-negative lung adenocarcinomas.
- To investigate the clinicopathologic features and prognostic impact of METex14 skipping.
- To explore the therapeutic potential of targeting METex14 skipping.
Main Methods:
- Screening of 45 quintuple-negative lung adenocarcinomas from 795 East Asian patients for METex14 skipping using reverse-transcriptase polymerase chain reaction.
- Investigating the effect of small interfering RNA (siRNA) targeting the METex14 skipping junction in cell lines.
Main Results:
- METex14 skipping was identified in 37.8% (17/45) of patients, predominantly older individuals with acinar or solid subtypes.
- MET immunohistochemistry showed 100% sensitivity and 70.4% specificity.
- Patients with METex14 skipping had a higher recurrence rate but similar overall survival compared to those with ALK fusion, after adjusting for pathologic stage.
Conclusions:
- METex14 skipping is highly prevalent in East Asian lung adenocarcinomas without other driver mutations.
- METex14 skipping is associated with specific clinicopathologic features and has a prognosis comparable to major driver mutations.
- siRNA targeting the METex14 skipping junction effectively inhibited MET-driven signaling pathways and cell proliferation in resistant cell lines.
