Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Age at diagnosis and anatomic distribution of NTRK3-fused Spitz tumors.
Fig. 2: Spitz melanocytomas (atypical Spitz tumors) with ETV6-NTRK3 fusion.
Fig. 3: Melanocytic tumors with MYO5A-NTRK3 fusion display unique histopathologic features.
Fig. 4: Melanomas with MYO5A-NTRK3 fusion demonstrate nodules of spindled melanocytes with a fascicular growth pattern and areas of marked cytologic atypia.
Fig. 5: Architectural and cytologic features of melanocytic tumors with MYH9-NTRK3 fusion.
Fig. 6: NTRK3 fusions contain different portions of NTRK3 and have distinct subcellular localizations.


  1. 1.

    Schram AM, Chang MT, Jonsson P, Drilon A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol. 2017;14:735–48.

    CAS  Article  Google Scholar 

  2. 2.

    Wiesner T, Murali R, Fried I, Cerroni L, Busam K, Kutzner H, et al. A distinct subset of atypical spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36:818–30.

    Article  Google Scholar 

  3. 3.

    Yeh I, Botton T, Talevich E, Shain AH, Sparatta AJ, de la Fouchardiere A, et al. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun. 2015;6:7174.

    Article  Google Scholar 

  4. 4.

    Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016;240:282–90.

    CAS  Article  Google Scholar 

  5. 5.

    Wang L, Busam KJ, Benayed R, Cimera R, Wang J, Denley R, et al. Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms. J Mol Diagn. 2017;19:387–96.

    CAS  Article  Google Scholar 

  6. 6.

    VandenBoom T, Quan VL, Zhang B, Garfield EM, Kong BY, Isales MC, et al. Genomic fusions in pigmented spindle cell nevus of reed. Am J Surg Pathol. 2018;42:1042–51.

    Article  Google Scholar 

  7. 7.

    Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20.

    CAS  Article  Google Scholar 

  8. 8.

    Yeh I, von Deimling A, Bastian BC. Clonal BRAF mutations in melanocytic nevi and initiating role of BRAF in melanocytic neoplasia. J Natl Cancer Inst. 2013;105:917–9.

    CAS  Article  Google Scholar 

  9. 9.

    Elder DE, Massi D, Scolyer R, Willemze R. WHO classification of skin tumours, 4th ed. Lyon, France: IARC Press; 2018.

  10. 10.

    Busam KJ, Kutzner H, Cerroni L, Wiesner T. Clinical and pathologic findings of Spitz nevi and atypical Spitz tumors with ALK fusions. Am J Surg Pathol. 2014;38:925–33.

    Article  Google Scholar 

  11. 11.

    Yeh I, de la Fouchardiere A, Pissaloux D, Mully TW, Garrido MC, Vemula SS, et al. Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions. Am J Surg Pathol. 2015;39:581–91.

    Article  Google Scholar 

  12. 12.

    Amin SM, Haugh AM, Lee CY, Zhang B, Bubley JA, Merkel EA, et al. A comparison of morphologic and molecular features of BRAF, ALK, and NTRK1 fusion spitzoid neoplasms. Am J Surg Pathol. 2017;41:491–8.

    Article  Google Scholar 

  13. 13.

    Yeh I, Busam KJ, McCalmont TH, LeBoit PE, Pissaloux D, Alberti L, et al. Filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize spitz tumors with NTRK1 fusion. Am J Surg Pathol. 2019;43:737–46.

    Article  Google Scholar 

  14. 14.

    Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction*. Annu Rev Biochem. 2003;72:609–42.

    CAS  Article  Google Scholar 

  15. 15.

    Yaar M, Eller MS, DiBenedetto P, Reenstra WR, Zhai S, McQuaid T, et al. The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes. J Clin Invest. 1994;94:1550–62.

    CAS  Article  Google Scholar 

  16. 16.

    Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–76.

    CAS  Article  Google Scholar 

  17. 17.

    Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34:599–608.

    Article  Google Scholar 

  18. 18.

    Del Castillo M, Chibon F, Arnould L, Croce S, Ribeiro A, Perot G, et al. Secretory breast carcinoma: a histopathologic and genomic spectrum characterized by a joint specific ETV6-NTRK3 gene fusion. Am J Surg Pathol. 2015;39:1458–67.

    Article  Google Scholar 

  19. 19.

    Church AJ, Calicchio ML, Nardi V, Skalova A, Pinto A, Dillon DA, et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol Off J U S Can Acad Pathol Inc. 2018;31:463–73.

    CAS  Google Scholar 

  20. 20.

    Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol Off J U S Can Acad Pathol Inc. 2019;32:147–53.

    CAS  Google Scholar 

  21. 21.

    Farago AF, Taylor MS, Doebele RC, Zhu VW, Kummar S, Spira AI, et al. Clinicopathologic features of non-small-cell lung cancer harboring an NTRK gene fusion. JCO Precis Oncol. 2018;2018.

  22. 22.

    Yakushina VD, Lerner LV, Lavrov AV. Gene fusions in thyroid cancer. Thyroid. 2017;28:158–67.

    Article  Google Scholar 

  23. 23.

    Chiang S, Cotzia P, Hyman DM, Drilon A, Tap WD, Zhang L, et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42:791–8.

    Article  Google Scholar 

  24. 24.

    Robinson CL, Evans RD, Sivarasa K, Ramalho JS, Briggs DA, Hume AN. The adaptor protein melanophilin regulates dynamic myosin-Va:cargo interaction and dendrite development in melanocytes. Mol Biol Cell. 2019;30:742–52.

    CAS  Article  Google Scholar 

  25. 25.

    Pastural E, Barrat FJ, Dufourcq-Lagelouse R, Certain S, Sanal O, Jabado N, et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet. 1997;16:289–92.

    CAS  Article  Google Scholar 

  26. 26.

    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    CAS  Article  Google Scholar 

  27. 27.

    Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    Article  Google Scholar 

  28. 28.

    Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220–2.

    CAS  Article  Google Scholar 

  29. 29.

    Bennett DC, Cooper PJ, Hart IR. A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth. Int J Cancer. 1987;39:414–8.

    CAS  Article  Google Scholar 

  30. 30.

    Korbel JO, Campbell PJ. Criteria for inference of chromothripsis in cancer genomes. Cell. 2013;152:1226–36.

    CAS  Article  Google Scholar 

  31. 31.

    Park H, Seo Y, Kim JI, Kim W, Choe SY. Identification of the nuclear localization motif in the ETV6 (TEL) protein. Cancer Genet Cytogenet. 2006;167:117–21.

    CAS  Article  Google Scholar 

  32. 32.

    Ménard M, Costechareyre C, Ichim G, Blachier J, Neves D, Jarrosson-Wuilleme L, et al. Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth. PLoS Biol. 2018;16:e2002912.

    Article  Google Scholar 

  33. 33.

    Mehta AD, Rock RS, Rief M, Spudich JA, Mooseker MS, Cheney RE. Myosin-V is a processive actin-based motor. Nature. 1999;400:590–3.

    CAS  Article  Google Scholar 

  34. 34.

    Trybus KM. Myosin V from head to tail. Cell Mol Life Sci CMLS. 2008;65:1378–89.

    CAS  Article  Google Scholar 

  35. 35.

    Yeh I, Mully TW, Wiesner T, Vemula SS, Mirza SA, Sparatta AJ, et al. Ambiguous melanocytic tumors with loss of 3p21. Am J Surg Pathol. 2014;38:1088–95.

    Article  Google Scholar 

  36. 36.

    Busam KJ, Sung J, Wiesner T, von Deimling A, Jungbluth A. Combined BRAF(V600E)-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol. 2013;37:193–9.

    Article  Google Scholar 

  37. 37.

    Wu X, Bowers B, Rao K, Wei Q, Hammer JA. Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function in vivo. J Cell Biol. 1998;143:1899–918.

    CAS  Article  Google Scholar 

  38. 38.

    Schlessinger J, Lemmon MA. Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Cell. 2006;127:45–8.

    CAS  Article  Google Scholar 

  39. 39.

    Lannon CL, Martin MJ, Tognon CE, Jin W, Kim S-J, Sorensen PHB. A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation. J Biol Chem. 2004;279:6225–34.

    CAS  Article  Google Scholar 

  40. 40.

    Tognon CE, Martin MJ, Moradian A, Trigo G, Rotblat B, Cheng S-WG, et al. A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation. Oncogene. 2012;31:1334–40.

    CAS  Article  Google Scholar 

  41. 41.

    Joo W, Hippenmeyer S, Luo L. Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling. Science. 2014;346:626–9.

    CAS  Article  Google Scholar 

  42. 42.

    Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, et al. Genetic heterogeneity of BRAF fusion kinases in melanoma affects drug responses. Cell Rep. 2019;29:573–88.e7.

    CAS  Article  Google Scholar 

Download references


SP was supported by a grant from the European Academy of Dermatology and Venereology (RF-2017-17). This work was supported by the National Cancer Institute at the National Institutes of Health (Grant Number 1R35CA220481). Immunofluorescence imaging was done at the Nikon Imaging Center, UCSF.

Author information



Corresponding author

Correspondence to Iwei Yeh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de la Fouchardière, A., Tee, M.K., Peternel, S. et al. Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes. Mod Pathol 34, 735–747 (2021).

Download citation


Quick links