Clinical and genetic characteristics of -mutated non-uveal and uveal melanoma.

Background: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized.

Methods: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome.

Results: mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. and mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with , V600 and Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating mutations.

Conclusion: In contrast to uveal melanomas, where mutations serve as a significant prognostic indicator of an unfavorable outcome, mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.