The role of gene fusions in melanocytic neoplasms

Abstract

Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are costeffective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies. K E Y W O R D S fusions, genomics, melanocytic lesions, melanoma, spitzoid 2 | MECHANISM OF FUSIONS Kinase fusions result from genomic rearrangements: (a) translocations, (b) inversions, (c) deletions, (d) duplications, or (e) complex Victor L. Quan and Elnaz Panah should be considered joint authors.

Expanding spectrum of “spitzoid” lesions: a small series of 4 cases with MAP2K1 mutations

“…It was known that about 20% of the spitzoid tumors carry an HRAS mutation [ 1 ]. More recently, chromosomal rearrangement-induced fusions have been identified in 50 to 55% of spitzoid lesions involving the kinase genes ROS1 , ALK , BRAF , NTRK1 , NTRK3 , MET , and RE T [ 2 , 3 ]. While the genetics of a significant portion of spitzoid neoplasms has been identified, in a significant portion of cases, the driver event is still unknown.…”

The WHO 2018 Classification of Cutaneous Melanocytic Neoplasms: Suggestions From Routine Practice

“…-The anti BRAF-mutated protein VE1 antibody identifies the subset of melanocytic tumors of the "classical" type harboring the BRAF v600e mutation (or a "combined" melanocytoma) (48, 81); -The immunostain for BAP1 can document loss of the consitutive nuclear immunoreactivity in BAP1-inactivated melanocytic tumors (33,34); -The anti PRAME immunostain can assist the differential diagnosis between benign and malignant "traditional" melanocytic tumors (82); in our experience, particularly for lentiginous neoplasms and for the differential diagnosis between congenital nevus and nevoid melanoma; -The anti-ALK, anti-TRKA, anti-MET, anti-HRAS-WT, and anti-ROS1 antibodies identify the subset of melanocytic tumors of the Spitz lineage with the respective kinase gene changes (48,83,84); ; provisionally defined as tumors with unknown driver mutations); ii) among melanocytomas, the distinction between low-grade and highgrade tumors; iii) among MELTUMP, the distinction between tumors with a low tumor mutation burden and tumors with a a high tumor mutation burden, the latter being best managed as per "classical" melanoma.…”

Testing forBRAFfusions in patients with advancedBRAF/NRAS/KITwild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy

“…Kinases fusions are more frequent in melanocytic Spitzoid tumours (including Spitzoid melanomas) than in non-Spitzoid ones and specific histopathological features have been described in the skin melanocytic tumours containing the different kind of kinases rearrangements 15–19. Although Spitzoid morphology can facilitate the prioritising of molecular testing of primary melanomas, the metastases may not share the same Spitzoid histopathological features and, therefore, may not suggest an associated kinase rearrangement.…”