Molecular characterization of MET fusions from a large real-world Chinese population: A multicenter study

Abstract

Purpose: MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real-world Chinese cancer population. Methods: We retrospectively included patients with solid tumors who had DNA-based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusion-positive (MET+) patients were subsequently selected for clinical and molecular characterization. Results: We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%–0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification. Conclusion: To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.