Characterization of MET exon 14 skipping in Chinese non-small cell lung cancer (NSCLC) patients.

Abstract

e21525 Background: MET exon 14 skipping ( METex14) has been identified as a precise biomarker for MET-targeted therapy. Most METex14 alterations occur in patients (pts) with non-small cell lung cancer (NSCLC). Here, we present the clinical, pathological, and genomic characteristics of Chinese NSCLC pts harboring METex14. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples from 3433 pts were collected from December 2017 to January 2019 for a 450 cancer gene targeted next-generation sequencing (NGS) panel. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions (Indels), copy number variations, and gene rearrangements were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A total of 35 (1.0%) pts harbored the GAs predicted to cause METex14, which was lower than that of the Western population (3%), and comparable to data in previously reported Chinese NSCLC pts. METex14 mutation rates were 10.5% in sarcomatoid carcinoma, 1.5% in adenosquamous carcinoma and 1.0% in adenocarcinoma. The median age of pts with METex14 was 65 years (range 46-85) and 46% were female. Compared with wild-type (WT) pts, those harboring METex14 were significantly associated with older age (median age: 65 vs. 60 years, respectively, p = 0.005) and earlier stage (stage I & II ratio: 67.7% vs 42.0%, respectively, p < 0.0001). METex14 alterations included 17 samples (48.6%) that were base substitutions located on the non-coding adjacent splice acceptor (1), donors (7), and other splice acceptors (9), and 18 (48.6%) Indels located on the non-coding adjacent splice acceptors (8), donor (1), other splice acceptor (1), and exon/intron junctions (7). MDM2, FRS2, and CDK4 amplification was observed in 22.9%, 20.0%, and 17.1%, respectively, of pts with METex14, which was significantly higher than in WT pts (P < 0.001). Concurrent EGFR mutations were rarely observed with METex14 compared with WT pts (8.6% vs. 51.7%, respectively, p < 0.0001). Concurrent MET amplification was identified in 3 samples with METex14, and no other driver genes were found. Conclusions: METex14 occurred in 1.0% of Chinese NSCLC pts and showed a significantly higher prevalence in sarcomatoid carcinoma. METex14 observed in pts with NSCLC were associated with increased concurrent MDM2, FRS2, and CDK4 amplification and decreased EGFR mutation, suggesting that METex14 acts as a driving oncogenic factor in NSCLC.