Distinct MET Protein Localization Associated With MET Exon 14 Mutation Types in Patients With Non–small-cell Lung Cancer

Abstract Background The MET gene has been recognized as a potential important therapeutic target in non–small-cell lung cancer (NSCLC). We sought to investigate the MET exon 14 mutations in a cohort of Chinese patients with NSCLC. Methods We tested 461 NSCLCs for MET exon 14 mutations by sequencing whole exon 14 and its flanking introns. The protein expression was determined by immunohistochemical analysis. Results In this study, we identified MET exon 14 mutations in 9 (2.0%) of 461 NSCLCs. Of these 9 mutations, 7 (77.8%) were located in the splice sites of MET exon 14, with MET overexpression in 6. One point mutation c.3010C>T (p.Arg1004Ter) was nonsense mutation with no MET expression. One insertion mutation was within exon 14 of MET with MET overexpression. MET protein localization in tumor cells with MET exon 14 mutations was different between mutation types. Three point mutations that disrupted the splice donor site of intron 14 were membranous staining, whereas the other mutations were cytoplasmic staining. Patients with MET exon 14 splice site mutations were significantly older. The incidence of MET exon 14 mutations in sarcomatoid carcinoma was significantly higher than in other histologic types (P = .034). Conclusion Distinct MET protein localization is associated with MET exon 14 mutation types in patients with NSCLC. Different MET exon 14 mutation types were identified in a subset of Chinese patients with NSCLC who could possibly benefit from MET targeted therapy.