ABSTRACT
Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Discoidin Domain Receptor 2/genetics , Molecular Motor Proteins/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Nevus, Epithelioid and Spindle Cell/enzymology , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Skin Neoplasms/enzymology , Adolescent , Adult , Aged , Child , Child, Preschool , Comparative Genomic Hybridization , Discoidin Domain Receptor 2/metabolism , Female , Humans , Male , Melanoma/enzymology , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Molecular Motor Proteins/metabolism , Myosin Heavy Chains/metabolism , Myosin Type V/metabolism , Nevus, Epithelioid and Spindle Cell/genetics , Nevus, Epithelioid and Spindle Cell/pathology , Oncogene Fusion , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-ets/metabolism , Repressor Proteins/metabolism , Sequence Analysis, DNA , Sequence Analysis, RNA , Skin Neoplasms/genetics , Skin Neoplasms/pathology , ETS Translocation Variant 6 ProteinABSTRACT
Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours 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.
Subject(s)
Gene Rearrangement , Melanoma, Experimental/genetics , Nevus, Epithelioid and Spindle Cell/genetics , Oncogene Fusion , Proto-Oncogene Proteins c-met/genetics , Adult , Animals , Cell Line , Female , Humans , Male , Mice , Middle AgedABSTRACT
Germline loss-of-function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of 1 allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus-like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.
