Spitz tumors and melanomas with MET fusion. Homo sapiens

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist. Overall design: The UCSF dermatopathology array comparative genomic hybridizaton database consists of copy number profiles of difficult to classify tumors obtained in the course of clinical practice. These cases were noted to have either a copy number transition within MET with relative gain of the 3' end of the gene or gain of the distal portion of chromosome 7q. There are 6 cases in this series, with one replicate each.