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Updated: May 27, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Pan-Cancer Analysis of Oncogenic MET Fusions Reveals Distinct Pathogenomic Subsets with Differential Sensitivity to
Christopher A Febres-Aldana1,2, Morana Vojnic3,4, Igor Odintsov5
1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
MET fusions (MET-F) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA sequencing plus 11,255 RNA sequencing) uncovered two forms of MET-F pathobiology. The first group featured 5' partners with homodimerization domains fused in-frame with the MET tyrosine kinase domain, primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in preclinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with receptor tyrosine kinase co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET TKI sensitivity are determined by structural topology and pathogenomic context.
Significance:
MET fusions are primary drivers of tumor growth in multiple tumor types - lung cancer and gliomas - and can be effectively targeted with either type I (crizotinib, capmatinib, tepotinib, and savolitinib) or type II (cabozantinib) MET TKIs, with best responses in tumors harboring fusions with partner homodimerization.
Insights
MET fusions drive tumor growth and can be targeted by MET tyrosine kinase inhibitors (TKIs). Understanding MET fusion structure reveals sensitivity to TKIs in lung cancer and gliomas.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- MET fusions (MET-F) are oncogenic drivers with poorly understood pathobiology.
- MET-F drives tumor growth in lung cancer and gliomas.
- MET-F can be targeted by MET tyrosine kinase inhibitors (TKIs).
Purpose of the Study:
- To characterize the heterogeneous landscape of MET fusions.
- To understand the structural basis of MET fusion oncogenicity and TKI sensitivity.
Main Methods:
- Analysis of 56 MET-F positive tumors from a large institutional cohort (91,119 patients).
- Utilized DNA and RNA sequencing data.
- Correlated fusion partners, structural topology, and pathogenomic context with TKI sensitivity.
Main Results:
- Identified two distinct MET-F pathobiology groups based on 5' partner domains and rearrangement types.
- Group 1: Homodimerization domains, translocations, excluded MET exon 14, cytoplasmic aggregation, sensitive to MET TKIs (lung cancer).
- Group 2: Lacked homodimerization motifs, intrachromosomal rearrangements, promoter hijacking, enriched in gliomas, retained MET domains.
Conclusions:
- Fusion oncogenicity and MET TKI sensitivity are determined by structural topology and pathogenomic context.
- Provides a framework for understanding MET-F heterogeneity.
- Highlights differential TKI sensitivity based on MET fusion subtypes.
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