A Complex Molecular Profile in Melanoma: Intratumoral Heterogeneity and Therapeutic Implications

Complex molecular alterations in cancers influence tumor biology, therapeutic response, and resistance. We report a case of cutaneous melanoma demonstrating extensive intratumoral heterogeneity with important clinical implications. A 77-year-old man with stage IIA cutaneous melanoma developed an isolated nodal recurrence one year after resection. Comprehensive next-generation sequencing of the metastatic lesion revealed an uncommon genomic profile consisting of a class 3 BRAF Y472V mutation, two NF1 loss-of-function mutations, and two concurrent KIT mutations: a dominant, potentially targetable K642E mutation and a low-frequency D816V mutation associated with resistance to tyrosine kinase inhibitors. The tumor exhibited a high tumor mutational burden and microsatellite stability. The patient received neoadjuvant nivolumab plus relatlimab followed by surgical resection, achieving complete pathologic response. Repeat sequencing of the resected specimen demonstrated complete molecular clearance of all previously detected variants. This case illustrates the value of comprehensive genomic profiling in revealing biologically complex melanoma with coexisting driver and resistance-associated alterations. The presence of a treatment-naïve KIT resistance mutation suggests preexisting subclonal heterogeneity that may influence future targeted therapy, while high tumor mutational burden and NF1 loss may have contributed to the excellent response to immune checkpoint blockade.