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 <i>NRAS</i> mutations were found in 42% of cases, <i>KRAS</i> mutations in 6%, and <i>KIT</i> mutations in 6% of cases. Remarkably, no <i>BRAF</i> mutations were detected. Patients with <i>NRAS</i>-mutated/<i>KRAS</i>-wild type (wt) melanomas showed better outcome than patients with <i>NRAS</i>-wt/<i>KRAS</i>-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.