Dynamic Evolution of Clonal Composition and Neoantigen Landscape in Recurrent Metastatic Melanoma with a Rare Combination of Driver Mutations.

In melanoma, initiating oncogenic mutations in BRAF or NRAS are detected in premalignant lesions that accumulate additional mutations and genomic instability as the tumor evolves to the metastatic state. Here we investigate evolution of clonal composition and neoantigen landscape in an atypical melanoma displaying recurrent cutaneous lesions over a 6-year period without development of extracutaneous metastases. Whole exome sequencing of four cutaneous lesions taken during the 6-year period identified a collection of single nucleotide variants and small insertions and deletions shared among all tumors, along with progressive selection of subclones displaying fewer single nucleotide variants. Later tumors also displayed lower neoantigen burden compared to early tumors, suggesting that clonal evolution was driven, at least in part, by counter selection of subclones with high neoantigen burdens. Among the selected mutations are a missense mutation in MAP2K1 (F53Y) and an inversion on chromosome 7 generating a AKAP9-BRAF fusion. The mutant proteins cooperatively activate the MAPK signaling pathway confirming they are potential driver mutations of this tumor. We therefore describe the long-term genetic evolution of cutaneous metastatic melanoma characterized by an unexpected phenotypic stability and neoantigen-driven clonal selection.