Mutational landscape of melanocytic tumors from patients with RASopathies

Summary: Abstract Body: RASopathies, including Neurofibromatosis 1 (NF1), Cardio-facio-cutaneous Syndrome (CFC), and Costello Syndrome (CS), are genetic syndromes characterized by germline pathogenic variants in genes of the RAS pathway. They are multi-systemic syndromes and often present with a cutaneous phenotype. Mutations in the RAS pathway also play a critical role in melanoma development, allowing for uncontrolled neoplastic growth. Approximately 80% of melanocytic nevi in the general population harbor the BRAF p.V600E somatic mutation, a common mutation in the RAS pathway. Despite this, the potential for additional somatic mutations of the RAS pathway in melanocytic tumors from RASopathy patients, and its role in melanoma risk, remains unexplored. In this study, we investigated the mutational landscape of melanocytic nevi in patients with NF1, CFC, CS, and controls. Whole exome sequencing was performed with tumor-normal or tumor-only analysis on 58 nevi (32 common, 24 dysplastic, 2 melanoma) from 58 patients (11 NF1, 3 CFC, 1 CS, 43 controls). A BRAF p.V600E somatic variant was found in 66% of the control nevi. In addition, the control nevi had an average of 0.52 somatic variants in the RAS pathway and cancer genes previously reported in melanoma on genomics databases (cBio, COSMIC). In comparison, only 28.6% of the RASopathy nevi harbored a BRAF p.V600E somatic variant. The RASopathy nevi had an average of 2.57 somatic variants in the RAS pathway and cancer genes previously reported in melanoma on genomics databases, compared to 0.52 variants in controls (p < 0.0003). This study explored the mutational landscape of melanocytic nevi from patients with RASopathies and controls and found increased somatic mutation burden in RAS pathway genes in RASopathy-associated nevi, leading to more insight into melanoma risk in RASopathies. Alexis E. Willy¹, Laura J. Young¹, Summer Meyer¹, Jennifer Tavernetti¹, Elanee Simmons¹, Katherine A. Rauen³, John D. McPherson², Maija Kiuru^{1, 4} 1. Dermatology, UC Davis Health, Sacramento, CA, United States. 2. Biochemistry and Molecular Medicine, UC Davis Health, Sacramento, CA, United States. 3. Pediatrics, UC Davis Health, Sacramento, CA, United States. 4. Pathology and Laboratory Medicine, UC Davis Health, Sacramento, CA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics