Recurrent hotspot SF3B1 mutations at codon 625 in vulvovaginal mucosal melanoma identified in a study of 27 Australian mucosal melanomas

INTRODUCTION: Clinical outcomes for mucosal melanomas are often poor due to a lack of effective systemic drug therapies. Identifying driver genes in mucosal melanoma may enhance the understanding of disease pathogenesis and provide novel opportunities to develop effective therapies. RESULTS: Somatic variant analysis identified SF3B1 (6 of 27: 22%) as the most commonly mutated gene, followed by KIT (3 of 27: 11%). Other less frequently mutated genes (4% otherwise stated) included BRAF (7%), NRAS (7%), ARID2, CTNNB1, DICER1, MAP2K1, NF1, PTEN, SETD2 and TP53. Recurrent SF3B1 p.R625 hotspot mutations were exclusively detected in vulvovaginal (5 of 19: 26%) and anorectal melanomas (3 of 5:60%). The only other SF3B1 mutation was a p.C1123Y mutation that occurred in a conjunctival mucosal melanoma. SF3B1-mutated patients were associated with shorter overall survival (OS; 34.9 months) and progression-free survival (PFS; 16.9 months) compared to non-SF3B1-mutated patients (OS: 79.7 months, log-rank P = 0.1172; PFS: 35.7 months, log-rank P = 0.0963). CONCLUSION: Molecular subgroups of mucosal melanoma with SF3B1 mutations occurred predominantly in the vulvovaginal region. SF3B1 mutations may have a negative prognostic impact. METHODS: Formalin-fixed biopsies were collected from 27 pathologically-confirmed mucosal melanomas. Genomic DNA was isolated from the tumor tissue and sequenced using a novel dual-strand amplicon sequencing technique to determine the frequency and types of mutations across 45 target genes.