Primary and Metastatic Melanoma With NTRK Fusions

Abstract

A number of oncogenic driver mutations have been identified in melanocytic nevi and melanoma, but translocations also play a role in tumorigenesis and provide potential therapeutic targets for malignant lesions. Various translocations, such as those involving the anaplastic lymphoma kinase (ALK), neurotrophic tropomyosin receptor kinase 1 (NTRK1), and NTRK3 have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK or NTRK expression. We have previously reported that ALK expression can be found in nonspitzoid primary and metastatic cutaneous melanomas. In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1, 1 involving NTRK2. They occurred in 3 women and 1 man. Two of the corresponding primary tumors were from the trunk, 1 from an extremity and 1 tumor arose in anal skin. One primary tumor displayed features of superficial spreading melanoma and 3 were nodular melanomas. All tumors were cytologically characterized by the presence of large epithelioid melanocytes. All tumors were immunoreactive with anti-Trk antibody. Next-generation sequencing documented that the NTRK1 fusion partners included TRIM63, DDR2, and GON4L. One tumor harbored an NTRK2-TRAF2 fusion. Thus, our findings document that NTRK kinase fusions can occur in nonspitzoid metastasizing melanomas of adults. The presence of an NTRK family fusion in these tumors may provide a therapeutic opportunity in a small subset of patients with metastatic melanoma.

ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research

“…Different antibodies are available to detect TRK expression in tissue samples. There are antibodies directed against specific NTRK proteins (TRKA or TRKB) [16,30,36], antibodies targeting an amino acid sequence common to TRKA, TRKB and TRKC (pan-TRK antibodies) [37][38][39][40] or a pan-TRK antibody cocktail [41]. Positive controls for IHC include the cell lines KM12 (TPM3-NTRK1) [36], MO-91 (ETV6-NTRK3) and CUTO-3.29 (MPRIP-NTRK1) [42], and formalin-fixed, paraffin-embedded (FFPE) cell pellets can be used as external controls in immunohistochemical runs [43].…”

“…Some studies have been based on the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT TM ) assay, a deep-coverage hybridisation capture-based assay encompassing the entire coding regions and selected intronic and regulatory regions of >400 key cancer genes [30,39]. This tumour-profiling multiplex panel has been recently cleared by the United States FDA as an in vitro diagnostic test that can identify somatic genetic alterations.…”

“…A study focussed on MSK-IMPACT applied to the analysis of 449 melanoma patients revealed four cases (0.9%) harbouring NTRK fusion genes; in three of these cases, the 3 0 partner was NTRK1, whereas in the remaining melanoma, NTRK2 was rearranged [30].…”

“…genetic alterations affecting the most common driver genes belonging to the MAPK signalling pathway (e.g. KRAS, NRAS and BRAF) [29][30][31][32]. They have also been reported as significantly more frequently encountered in microsatellite instability (MSI)high tumours in the context of colorectal carcinoma patients [31].…”

Melanomas with activating RAF1 fusions: clinical, histopathologic, and molecular profiles

“…Kinase rearrangements, although less common, represent the oncogenic drivers in emerging subgroups of melanoma, often through activation of MAP kinase pathways. Rearrangements in several genes, including BRAF, RET, ROS1, ALK, NTRK1, and NTRK3, have been characterized in subsets of melanoma [2][3][4][5]. Surprisingly, despite the central role of RAF1 in the MAP kinase pathway, there are only isolated reports of RAF1 (CRAF) fusions in melanomas, and the histopathologic characterizations of these tumors have been limited [6][7][8].…”