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

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. 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). Molecular subgroups of mucosal melanoma with SF3B1 mutations occurred predominantly in the vulvovaginal region. SF3B1 mutations may have a negative prognostic impact. 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.