A review of kinase fusions in melanocytic tumors

Abstract

Translocations resulting in a kinase fusion are well reported in many tumor types and indeed can be defining, particularly in the case of hematopoietic malignancies. The recent reports of multiple protein kinase fusions within melanocytic neoplasms, particularly in those with spitzoid morphology, have heralded a new era of classification of these melanocytic tumors. Seen within approximately half of all spitzoid neoplasms and present within the full spectrum of benign, atypical, and malignant lesions, kinase fusions likely represent an early oncogenic event contributing to cell proliferation and growth. Although the presence of a kinase fusion does not seem to correlate with the biologic potential of a given lesion, documentation of a kinase fusion will likely be important, particularly in the case of spitzoid melanoma, as numerous specific kinase receptor inhibitors have shown promise as therapeutic agents in a subset of cases with kinase fusions. Interrogation of non-spitzoid melanomas for similar kinase fusions as a potential driving oncogenic mechanism has revealed some similarities and some differences. This review will focus on the kinase fusions described to date in spitzoid neoplasms and how subsequent studies have informed current melanoma research.

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.…”

Spitzoid Melanoma-Case Report; Potential Role of Alk Expression in the Diagnosis of Spitzoid Melanocytic Lesions

“…Later, it was identifi ed in other neoplasms, either benign or malignant, such as lung adenocarcinoma, Ewing sarcoma, infl ammatory myofbroblastic tumor, epithelioid fi brous histiocytomas (22). ALK was also detected in approximately 10-15% of all spitzoid tumors; ALK fusions are found in benign Spitz naevi, atypical Spitz tumors, and less commonly in spitzoid melanoma (23)(24)(25)(26). Immunohistochemistry is widely considered a good surrogate for ALK rearrangement (5,27).…”

Dysplastic/Clark naevus in the era of molecular pathology

“…Genomic alterations in well‐recognised histopathological subtypes of melanocytic naevi are also different from those of dysplastic naevus. For example, naevi with spitzoid morphology, which may occasionally show overlapping histopathological features with dysplastic naevus, exhibit distinct molecular alterations including kinase (ALK, BRAF, RET, NTRK1, ROS1, MET and PRKCA) fusions; bi‐allelic BAP1 inactivation; and HRAS mutations with or without gain of chromosome 11p . Other morphologic variants of naevi such as blue naevi and deep penetrating naevi show initiating mutations in GNAQ/GNA11 and combined mutations in BRAF and CTNNB1 or APC genes, respectively .…”