MET amplification and exon 14 skipping are well known as oncogenic drivers in multiple cancer types. However, MET fusions in most cancer types are poorly defined. To explore the profile and analyze the characteristics of MET fusions, a large-cohort study was conducted to screen MET fusions in clinical samples (n = 10 882) using DNA-based NGS. A total of 37 potentially functional MET fusions containing the intact tyrosine kinase domain (TKD) of MET were identified in 36 samples. Further, 15 novel MET fusions were identified in five cancer types, and the incidence of novel MET fusions accounted for 40.5% (15/37). Brain cancer had the highest incidence of MET fusion, with PTPRZ1-MET as the most common fusion (37.0%). All MET breakpoints in brain cancer (n = 27) were also located in intron 1, while those in lung cancer (n = 4) occurred in intron 1, intron 11, intron 14 and exon 14, respectively. The positive consistency of the common fusion group was 100% (11/11), while that of the rare fusion group was 53.8% (7/13). In conclusion, we provided a comprehensive genomic landscape of MET rearrangement and updated the MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.
Keywords: DNA/RNA-based NGS; common MET fusions; novel MET fusions; rare MET fusions; tyrosine kinase domain.
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