Pan-Cancer Analysis of Oncogenic MET Fusions Reveals Distinct Pathogenomic Subsets with Differential Sensitivity to...

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.