Abstract

Introduction: Though uncommon in melanoma, gene fusions often have therapeutic implications and may be indicative of treatment resistance. Methods: Next generation sequencing (NGS)-based assays designed to detect relevant translocations/fusions in RNA and mutations and copy number changes in genomic DNA were performed on 751 consecutive clinical cases (376 primary and 375 metastases) at our institution from 2014-2021. The melanomas included 599 (80%) cutaneous cases, 38 (5%) acral, 11 (1.5%) anorectal, 23 (3%) sinonasal, 27 (3.6%) eye (uveal/conjunctiva), 11 (1.5%) genital (vulva/penile), and 41 (5.5%) cases of unknown primary. Results: Seventeen fusions were detected in 6 primary tumors and 13 metastases of 17 patients: 13/599 (2.2%) cutaneous, 2/38 (5%) acral, 1/9 (11%) vulva, 1/23(4.3%) sinonasal. Twelve (71%) patients were male. We identified 4 novel fusions, which have been reported in other malignancies but not in melanomas: CANT1-ETV4 (prostate cancer), CCDC6-RET (thyroid cancer), MAGS-MAST2 and GNB1-NOTCH1 (breast cancer). Additional fusions involving ALK (EML4-ALK, MLPH-ALK), BRAF (AGAP3-BRAF, AGK-BRAK, CDH3-BRAF, CCT8-BRAF, DIP2B-BRAF), RAF1 (EFNB1-RAF1, LRCH3-RAF1, MAP4-RAF1, RUFY1-RAF1), MET (exon 14 skipping) and TERT (ADCY2-TERT) have been previously reported in melanomas. Importantly, 9/17 (53%) fusions (involving ALK, BRAF, RET and MET exon 14 skipping) may be amenable to treatment with targeted therapies approved for other indications. Mutational analysis identified 11/16 triple negative (BRAF, NRAS and NF1 wildtype) tumors. Fusion positive melanomas harbored recurrent mutations in APC, ATM, BRCA2, CDKN2A, CIC, KDR, MAP3K1, MEN1, MET, NF1, NF2, PIK3CA, SMARCB1, SMARCA4, TERT, TP53, TSC1, and TSC2. Conclusion: Rare fusions detected in melanoma might be of therapeutic relevance.

Financial Disclosure: No current or relevant financial relationships exist.