Melanoma With RNF11::BRAF Fusion: A Novel Fusion Previously Undescribed in Melanoma.

Abstract: B-Raf Proto-Oncogene (BRAF) fusions are rare in melanomas. We present a case of cutaneous melanoma with a Ring Finger Protein 11 (RNF11)::BRAF fusion in a 63-year-old man with a history of stage IB melanoma on the right upper back (pT2apN0cM0; nonulcerated with a Breslow thickness of 1.2 mm). Despite initial treatment, the melanoma progressed to multiple metastases. Histopathologically, the tumor cells exhibited epithelioid and rhabdoid morphologies, with occasional giant pleomorphic cells and multinucleation, and were positive for antimelanocytic cocktail (HMB45, Melan-A, tyrosinase) and S100. Next-generation sequencing of a metastatic specimen identified an RNF11::BRAF fusion and TERT promoter mutation, but no other somatic mutations (eg, BRAF, NRAS, KIT) or copy number variations were detected. The patient died to melanoma approximately 58 months after initial diagnosis, despite several lines of systemic therapy, including immunotherapies and a mitogen-activated protein kinases 1 and 2 inhibitor. RNF11::BRAF fusions are known oncogenic drivers in histiocytic disorders such as Erdheim-Chester disease and non-Langerhans cell histiocytosis. Although BRAF fusions are commonly observed in Spitz melanocytic neoplasms, the discovery of the RNF11::BRAF fusion in melanomas is unprecedented. Our case represents a triple wild-type, clinically aggressive melanoma of possibly non-Spitz lineage with an ultraviolet signature and a rare BRAF fusion, contributing to the expanding body of literature on BRAF-fused melanomas.