Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes

Abstract

A subset of Spitz tumors harbor fusions of NTRK3 with ETV6 , MYO5A , and MYH9 . We evaluated a series of 22 melanocytic tumors in which an NTRK3 fusion was identified as part of the diagnostic workup. Tumors in which NTRK3 was fused to ETV6 occurred in younger patients, were predominantly composed of epithelioid melanocytes, and were classified by their histopathologic features as Spitz tumors. In contrast, those in which NTRK3 was fused to MYO5A were predominantly composed of spindled melanocytes arrayed in fascicles with neuroid features such as pseudo-Verocay bodies. To further investigate the effects of the fusion kinases ETV6-NTRK3 and MYO5A-NTRK3 in melanocytes, we expressed them in immortalized melanocytes and determined their subcellular localization by immunofluorescence. ETV6-NTRK3 was localized to the nucleus and diffusely within the cytoplasm and caused melanocytes to adopt an epithelioid cytomorphology. In contrast, MYO5A-NTRK3 appeared excluded from the nucleus of melanocytes, was localized to dendrites, and resulted in a highly dendritic cytomorphology. Our findings indicate that ETV6-NTRK3 and MYO5A-NTRK3 have distinct subcellular localizations and effects on cellular morphology.

NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

“…Indeed, it has been suggested that the staining characteristics of pan-TRK IHC in NTRK fusion-positive tumors vary depending on fusion partners or tumor/tissue types. 22,50,51 According to recent reports, ETV6-NTRK3 fusion-positive tumors generally demonstrate nuclear to cytoplasmic staining of pan-TRK IHC in their tumor cells, and occasionally some ETV6-NTRK3 fusion salivary gland tumors show focal weak staining of pan-TRK IHC, similar to our cases. 21,22,50 Although the overall sensitivity of All rights reserved.…”

An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

“…In Spitz melanocytic proliferations, NTRK1 fusions predominate over NTRK3 fusions, the latter being more common in the pigmented spindle cell nevus of Reed, a special subtype of Spitz nevus (2,9,11,23,43,46,47,67,(69)(70)(71)(72)(73)(74). Only a single case of superficial spreading melanoma with an TRAF2-NTRK2 fusion has been reported so far (7).…”

“…While no NTRK1 fusions have been identified in Reed nevi, they harbor NTRK3 fusions (with MYO5A and rarely ETV6 fusion partners) in up to 57% of cases (67). In addition to pigmented spindle cell nevi of Reed, Spitz proliferations with NTRK3 fusions are usually diagnosed as Spitz nevi or atypical Spitz tumors and much less frequently as Spitz melanomas (9,67,69,70,73).…”

“…It has been recently demonstrated that various NTRK3 fusion partners have different intracellular localizations, ultimately determining the morphological characteristics of the Spitz melanocytes (62). For exam-ple, MYO5A-NTRK3 chimeric protein is localized to cell dendritic processes and is associated with a fusiform/spindled morphology of melanocytes with a fascicular or sometimes plexiform or syncytial growth pattern (70). Besides, the formation of pseudo-Verocay bodies or pseudorosettes is associated with a more neuroid appearance of these proliferations (70).…”

“…For exam-ple, MYO5A-NTRK3 chimeric protein is localized to cell dendritic processes and is associated with a fusiform/spindled morphology of melanocytes with a fascicular or sometimes plexiform or syncytial growth pattern (70). Besides, the formation of pseudo-Verocay bodies or pseudorosettes is associated with a more neuroid appearance of these proliferations (70). In contrast, the ETV6-NTRK3 chimeric protein is localized to both the nucleus and cytoplasm of melanocytes and is linked to an epithelioid morphology with well-defined cell borders.…”