KRAS/NRAS variants and copy number alterations prognostically stratify patients with sinonasal melanoma.

Sino-nasal mucosal melanoma (SN-MM) is an aggressive and rare form of melanoma arising from mucosal melanocytes with pathogenesis unrelated to sun exposure. Conversely to cutaneous melanoma (CM), the molecular bases underling SN-MM development and progression are unclear, and no molecular predictive markers have been identified yet. To better define the molecular landscape of SN-MM, a retrospective series of 37 SN-MMs from 31 patients was analysed for both somatic mutations and cytogenetic alterations. The somatic mutation analysis identified the presence of a driver gene pathogenic variant in 54% of cases. In detail, mutually exclusive NRAS mutations were found in 42% of cases, KRAS mutations in 6%, and KIT mutations in 6% of cases. Remarkably, no BRAF mutations were detected. Patients with NRAS-mutated/KRAS-wild type (wt) melanomas showed better outcome than patients with NRAS-wt/KRAS-mutated melanomas, which were associated with multiple recurrences at local or regional sites. On the other hand, focusing on genomic alterations, copy number variants (loss of 1p36, loss of 3p/3q) were identified in 19% of SN-MMs, which showed poor overall survival and short disease-free survival with early metastatic dissemination. This work describes a new integrated characterization of both single nucleotide variants and, for the first time, genomic alteration in SN-MM, providing a new insight into molecular bases of these neoplasms and prompting further efforts for personalized clinical protocols according to tumour aggressiveness.