Non-Small Cell Lung Carcinomas with MET Exon 2 Skipping Mutations: A Potential Inhibitory Self-Regulatory Mechanism by Tumor Cells

Document Type

Conference Proceeding

Publication Date

3-1-2024

Publication Title

Lab Invest

Abstract

Background: Activation of MET (Mesenchymal-Epithelial-Transition) oncogene represents an emerging molecular target for cancer treatment. MET is deregulated in diverse human tumors. Although the role of MET-exon-14 skipping mutations are well studied as a targetable mutation in non-small cell lung cancer (NSCLC), the role of MET-exon-2 skipping mutations in lung cancer have never been evaluated in literature. Design: ArcherDx 50-gene FusionPlex Solid Tumor Panel was performed to identify NSCLC with MET exon 2 skipping mutations. DNA alterations were also analyzed by Trusight 48-gene panel using Illumina MiSeq instrument and data analysis by Agilent Alissa platform. Patients with MET-exon-2 skipping mutations diagnosed with NSCLC in 2019 were retrospectively sorted out and their clinico-pathologic and molecular features were analyzed. Patients were clinically followed for 3 years via chart review. Results: MET Exon 2 skipping mutations were seen in one third of the tumors that underwent molecular testing by the ArcherDx Panel. Our patient cohort consisted of 40 patients (20 males and 20 females), who harbored NSCLC with MET exon 2 skipping mutations. Average age was 69.1 years (range: 42-90 y). 33 (82.5%) patients were smokers, and 38 (95%) had metastases at presentation. 29 (72.5%) were deceased by 3 years of follow-up. The average survival was 16.4 months after diagnosis in the deceased patients (See Table 1). There were Tier 1/ 2 mutations that co-existed with MET-exon-2 skipping mutations in 75% of cases, viz. KRAS (n=13), MET (n=11), BRAF (n=7), EGFR (n=6), TP53 (n=6), RET (n=3), VHL (n=2), STK11 (n=2), MLH1 (n=2), ERBB2 (n=1), and NRAS (n=1). Conclusions: MET-exon-2 skipping was documented as a potential self-regulating mechanism of tumor cells by decreasing abundance of Met mRNA encoding a functional Met receptor. Our findings suggest that advanced stage non-small cell lung carcinomas may trigger one such regulatory event to balance cancerous growth of tumor against coexisting pathogenic mutations especially of genes from the MAPK pathways. These observations are novel and may help shed light on mechanisms that regulate tumor growth, facilitate biomarker development for prognostics, and help design therapeutic targets.

Volume

104

Issue

3

First Page

S1945

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