Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type.,To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors.,Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2.,Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8.,SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas.,TERT aberrations and ATRX mutations are associated with alterations in telomere length.,Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.,Mucosal melanomas are challenging to treat partly because so little is known about the genetic drivers underpinning them.,Here, the authors perform a genomic landscape analysis of samples collected from three continents, revealing a potential role for CDK4/6 or MEK inhibition in the treatment of the disease.
Melanocytic proliferations are common in horses but the diagnosis of malignancy is not always straightforward.,To improve diagnosis and prognosis, markers of malignancy are needed.,Receptor for activated C kinase 1 (RACK1) protein may be such a marker.,RACK1 was originally found to characterize malignant melanocytic lesions in the Melanoblastoma-bearing Libechov minipig (MeLiM) and, later, in human patients.,Our purpose was to investigate the value of RACK1 in the classification of cutaneous melanocytic proliferations in horses.,Using immunofluorescence, we report here that both MITF (Microphthalmia-associated transcription factor) and PAX3 (Paired box 3) allow the identification of melanocytic cells in horse skin samples.,Importantly, RACK1 was detected in melanocytic lesions but not in healthy skin melanocytes.,Finally, we found that RACK1 labeling can be used in horses to distinguish benign melanocytic tumors from melanomas.,Indeed, RACK1 labeling appeared more informative to assess malignancy than individual histomorphological features.,This study confirms that horses provide an interesting model for melanoma genesis studies.,It establishes MITF and PAX3 as markers of horse melanocytic cells.,RACK1 emerges as an important marker of malignancy which may contribute to progress in the diagnosis of melanomas in both human and veterinary medicine.