Identification of NTRK3 fusions in childhood melanocytic neoplasms Journal Article


Authors: Wang, L.; Busam, K. J.; Benayed, R.; Cimera, R.; Wang, J.; Denley, R.; Rao, M.; Aryeequaye, R.; Mullaney, K.; Cao, L.; Ladanyi, M.; Hameed, M.
Article Title: 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. © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology
Keywords: adolescent; child; human tissue; preschool child; school child; unclassified drug; single nucleotide polymorphism; exon; case report; gene; gene amplification; melanocyte; protein tyrosine kinase; childhood cancer; genome analysis; oncogene; skin tumor; fluorescence in situ hybridization; gene rearrangement; hybrid protein; tumor recurrence; gene identification; gene fusion; fusion gene; dimerization; gene dosage; complementary dna; copy number variation; multiplex polymerase chain reaction; next generation sequencing; human; male; female; article; melanocytic neoplasm; myo5a ntrk3 protein; myo5a-ntrk3 fusion; ntrk3 gene
Journal Title: Journal of Molecular Diagnostics
Volume: 19
Issue: 3
ISSN: 1525-1578
Publisher: Elsevier Science, Inc.  
Date Published: 2017-05-01
Start Page: 387
End Page: 396
Language: English
DOI: 10.1016/j.jmoldx.2016.11.005
PROVIDER: scopus
PMCID: PMC5417047
PUBMED: 28433076
DOI/URL:
Notes: Article -- Export Date: 2 June 2017 -- Source: Scopus
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MSK Authors
  1. Meera Hameed
    136 Hameed
  2. Marc Ladanyi
    863 Ladanyi
  3. Lu Wang
    139 Wang
  4. Klaus J Busam
    536 Busam
  5. Ryan Denley
    7 Denley
  6. Long Cao
    8 Cao
  7. Mamta K Rao
    12 Rao
  8. Rym Benayed
    68 Benayed
  9. Jiajing Wang
    8 Wang
  10. Robert Sime Cimera
    8 Cimera