Oncogenic specificity in nevus and melanoma formation

There is striking clinical, histological, and molecular diversity observed across melanocytic tumors. Activating mutations in BRAF and NRAS are well-established initiators of benign melanocytic nevi and melanoma. However, accumulating evidence reveals that the biological outcome after oncogene activation is dependent on cellular state differences that vary by anatomic site, developmental timing, and cell of origin. Recent advances in genomic profiling and functional modeling have demonstrated that melanocytes are not a uniform cell population but exhibit site-specific transcriptional programs and differential transformation competence. Here, we synthesize current evidence from clinical, histological, and genomic studies to highlight the context-dependent effects of BRAF, NRAS, and other oncogenic mutations across melanocytic lesions with particular attention to cutaneous, acral, and mucosal sites.