Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms

Abstract

Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3. Break-apart fluorescence in situ hybridization confirmed the presence of NTRK3 rearrangement, and a novel MYO5A-NTRK3 transcript, representing an in-frame fusion of MYO5A exon 32 to NTRK3 exon 12, was identified using a rapid amplification of cDNA ends-based anchored multiplex PCR assay followed by next-generation sequencing. The predicted MYO5A-NTRK3 fusion protein consists of several N-terminal coiled-coil protein dimerization motifs encoded by MYO5A and C-terminal tyrosine kinase domain encoded by NTRK3, which is consistent with the prototypical structure of TRK oncogenic fusions. Our study also demonstrates how array-based copy number analysis can be useful in discovering gene fusions associated with unbalanced genomic aberrations flanking the fusion points. Our findings add another potentially targetable kinase fusion to the list of oncogenic fusions in melanocytic tumors.

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3‐SCAPER gene fusion

“…The functional significance of this inframe fusion, which is producing a truncated SCAPER protein is unclear and may be worthy of future study. We can only speculate as to why the NTRK3‐SCAPER fusion in this case was associated with PEM‐like morphology as opposed to pigmented Spitz nevus‐like morphology that has been described in prior series . In the case of PEM with a MYO5A‐NTRK3 fusion reported by Isales et al (2018), it is likely that the concomitant PRKAR1A mutation influenced the ultimate morphology .…”

“…A novel finding in this case is the detection of an in‐frame NTRK3‐SCAPER fusion. NTRK3 fusions (most often with a 5′ partner such as MYO5A or ETV6 ) have recently been reported to occur in the context of some pediatric Spitz nevi (especially pigmented nevus of reed variant) and atypical spitzoid tumors, To our knowledge, this particular fusion combination has not been reported previously in PEM or any other melanocytic neoplasm. The functional significance of this inframe fusion, which is producing a truncated SCAPER protein is unclear and may be worthy of future study.…”

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

“…Spitzoid tumors, a group of melanocytic lesions that are more common in children and adolescents, have been found to harbor NTRK1 fusions in approximately 16% of cases as well as NTRK3 fusions in a smaller subset of patients 17 …”

The role of gene fusions in melanocytic neoplasms

“…NTRK3 rearrangements are the single most common and characteristic fusion in PSCN of Reed, found in 57% of cases . A small number of predominantly spindle cell Spitz nevi and ASTs may also have NTRK3 fusions …”