Molecular Investigation of Metastatic Sinonasal Mucosal Melanoma

Sinonasal mucosal melanoma (SNMM) is a rare high-grade malignancy involving the sinonasal tract, primarily including the nasal cavity, turbinates, nasopharynx, and paranasal sinuses. The 5-year survival rate is less than 30% due to its advanced clinical presentation and frequent late-stage diagnosis, which is even worse in SNMM patient with distant metastatic disease. This underscores the critical need for investigating molecular profiles and identifying potential therapeutic strategies for metastatic SNMM. In this study, we used sequencing techniques to investigate distinct molecular profiles of metastatic SNMM and explores potential therapeutic strategies for metastatic SNMM patients. First, overall survival analysis revealed that SNMM patients with metastasis exhibited significantly poorer overall survival compared to non-metastatic patients (median survival: 18.8 vs 38.7 months). Our preliminary NGS data further identified missense mutations in SLX4 gene as being exclusively detected in metastatic SNMM. These mutations were associated with significantly shorter survival (median: 9.9 vs. 34.2 months). Notably, all three patients with SLX4 mutations died 2.4, 9.9 and 28.1 months, respectively. In addition, a comparative analysis of genomic alterations of clinically relevant genomic alterations (CRGAs) that are defined as genomic alterations (GAs) linked to available or investigational targeted therapies between metastatic and non-metastatic SNMM revealed that CDK4 gains/amplifications targeted by a selective CDK4/6 inhibitor, such as Palbociclib, were commonly seen in metastatic cases. Collectively, these exploratory findings suggest SLX4 mutation as a potential prognostic marker and CDK4 inhibitors as promising therapeutic options for metastatic SNMM.