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

Abstract

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.

MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology

“…MAP2K1 alterations have been reported among 0.5%-7% of primary and metastatic melanomas, consisting mostly of RAF-dependent and RAF-regulated alterations. 21,[34][35][36][37][38][39] Recently, 37 primary and metastatic melanomas harboring MAP2K1 in-frame deletions have been detected in a cohort of 7119 advanced melanomas. All these alterations involved the kinase domain locus of MAP2K1 corresponding to class III MAP2K1 mutations (RAF-independent) except for 6 cases characterized by c.173_187del, p.(Gln58_Glu62del).…”

“…MAP2K1 alterations have been reported among 0.5%–7% of primary and metastatic melanomas, consisting mostly of RAF-dependent and RAF-regulated alterations. 21,34–39…”

Tumor neoantigens: from basic research to clinical applications

“…Tumors with high or heterogeneous levels of immune cell infiltration had significantly lower levels of expressed clonal neoantigens than those with limited levels of infiltration (median 29% and 35% versus 41%; P < 0.01). The pattern of neoantigen quantity and/or quality changes reflecting the immunoediting was also observed in other solid tumors including pancreatic cancer [79], colorectal cancer [74], melanoma [75], and glioblastomas [78].…”

Proteogenomic analysis unveils the HLA Class I presented immunopeptidome in melanoma and EGFR mutant lung adenocarcinoma

“…Nevertheless, a majority of studies have focused on "hot" tumors, such as melanoma or other high TMB lung cancer types 16,53 . The "cold tumors" that have a paucity of TILs, tumors with low TMB such as EGFR mutant lung cancer and tumors with loss of neoantigen expression while on immunotherapy are relatively resistant to immune checkpoint therapy [54][55][56][57] . In this study, it was our intent to leverage proteogenomics and informatics to identify HLA Class I-presented peptide antigens, including neoantigens, common driver oncogenes, CG antigens, posttranslationally modified peptides and LncRNA -translated protein products, for immunotherapy in low TMB "cold" EGFR mutant lung adenocarcinoma.…”