Track: Basic Science

Abstract:

RASopathies, including Neurofibromatosis 1 (NF1), Cardio-facio-cutaneous Syndrome (CFC), and Costello Syndrome (CS), result from germline pathogenic variants in RAS pathway genes. These syndromes are multi-systemic, often presenting with distinctive cutaneous features. In contrast, melanocytic tumors in the general population typically arise from somatic driver mutations in the RAS pathway, with the BRAF V600E mutation specifically present in approximately 50% of melanomas. BRAF V600E is also the predominant driver mutation in nevi, but roughly 20% lack this alteration, indicating alternative somatic drivers. The potential for additional somatic RAS pathway mutations in nevi from patients with germline RAS pathway mutations (RASopathies), and their implications for melanoma risk, remain unexplored. We characterized the mutational landscape of nevi in patients with NF1, CFC, CS, and in controls without clinical or genetic features of RASopathies. Whole-exome sequencing was performed with tumor-normal or tumor-only analysis on 50 nevi (29 common, 21 dysplastic) from 50 patients (3 NF1, 3 CFC, 1 CS, 43 controls). The BRAF V600E somatic variant was found in 66% (30/43) of control nevi versus 28.6% (2/7) of RASopathy nevi. RASopathy nevi harbored significantly more melanoma-associated variants in RAS and cancer genes compared to controls (p = 0.0032). Tumor mutation burden (total somatic coding mutations per megabase) did not significantly differ between RASopathy nevi and controls (p = 0.83), indicating similar overall mutation counts. Nonetheless, RASopathy nevi demonstrated distinct enrichment for melanoma-associated variants in RAS and cancer genes, underscoring that their mutational divergence reflects qualitative rather than quantitative differences in oncogenic alterations.

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Jennifer Tavernetti