1644 MET Exon 2 Skipping (METEx2) Mutation, a Tumor Self-Regulatory Mechanism, is Associated with Co-Existing Actionable MAP Kinase Pathway Gene Mutations, and Adverse Histology Patterns in Advanced Stage Non-Small Cell Lung Carcinomas (NSCLC): A Study of 111 Cases with METEx2 Mutation

Document Type

Conference Proceeding

Publication Date

3-23-2026

Publication Title

Lab Invest

Keywords

epidermal growth factor receptor, messenger RNA, mitogen activated protein kinase, scatter factor receptor, adult, apoptosis, clinical article, cohort analysis, conference abstract, controlled study, diagnosis, drug therapy, exon, female, gene expression, gene mutation, giant cell, high throughput sequencing, histology, human, human tissue, lung biopsy, major clinical study, male, neoplastic cell transformation, non small cell lung cancer, radiotherapy, retrospective study, surgery, survival analysis, tumor growth

Abstract

Disclosures: Ejas Palathingal Bava: None; Akram Aldilaimi: None; Omar Abbas: None; Kasturi Saikia: None; Joseph Montecalvo: None; Zhiqiang Wang: None Background: MET activation is an actionable oncogenic driver for NSCLC. MET exon-2 skipping (METex2) mutations lead to formation of a truncated Met protein without an extracellular domain, resulting from a Met mRNA that fails protein translation and hence were documented as a post-transcriptional self-regulatory mechanism by tumor cells to limit Met receptor expression, with functional consequences that are not well studied. The aim of this study was to: 1) investigate the co-existing significant mutations delineated by the number of patients with METex2 mutation in NSCLC in a large cohort of 111 patients, 2) evaluate the co-existing actionable mutations in KRAS and EGFR, and 3) to evaluate their histology in a subset of 22 patients. Design: NGS results of patients who underwent molecular testing for NSCLC from 2018 to 2020 were reviewed and patients with METex2 mutation were retrospectively segregated. Their molecular features, histology and survival analysis were deciphered in all cases harboring the METex2 mutation. Histological features of lung biopsy slides with adenocarcinomas were evaluated in a subset of 22 available cases from 2019. Results: The 111 patients with NSCLC harboring METex2 mutation had poor survival (Fig1A) and 77.5% of the patients had adenocarcinomas (Table 1). Treatment received included surgery (29.4%), chemotherapy / immunotherapy (72.5%) and radiotherapy (55.9%). When delineated by number of patients (n) harboring co-existing Tier 1 /2 mutations, KRAS (n=40), EGFR (n=16), BRAF (n=10), MET7 (n=8), TP53 (n=7), NRAS (n=5), ERBB2 (n=2) and MET Exon 14 skipping (n=2) mutations were the most common (Fig.1B-C). Co-existing actionable mutations in KRAS and EGFR were seen 30 times, with KRAS G12C being the most common (n=15) (Fig.1D). Microscopically, the tumors showed solid (n=13)(A), micropapillary (n=6)(B), cribriform (n=4)(C), acinar (n=4)(D), giant cell (n=3)(E), mucinous (n=2)(F), lepidic (n=1), rhabdoid (n=1), hepatoid (n=1) and clear cell features (n=1) (Fig.2A-F) (>1 pattern in n=10, one case showing 5 patterns). [Formula presented] [Formula presented] [Formula presented] Conclusions: Our findings in a large cohort of patients with METex2 mutations, showing it’s association with coexisting Tier 1 /2 mutations in genes from the MAPK pathway (KRAS, EGFR, BRAF), many actionable mutations and adverse histology patterns are striking. Findings indicate presence of a threshold at which tumor cells activate self-regulatory mechanism to prevent triggering apoptotic process, to rein in cancerous growth, and for balanced tumor progression.

Volume

106

Issue

3

Find It @ Sladen

Share

COinS