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

Camelia Quek; Robert V Rawson; Peter M Ferguson; Ping Shang; Ines Silva; Robyn P M Saw; Kerwin Shannon; John F Thompson; Nicholas K Hayward; Georgina V Long; Graham J Mann; Richard A Scolyer; James S Wilmott

doi:10.18632/oncotarget.26584

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

Oncotarget. 2019 Jan 29;10(9):930-941. doi: 10.18632/oncotarget.26584.

Authors

Camelia Quek^{1

2}, Robert V Rawson^{1

2

3}, Peter M Ferguson^{1

2

3}, Ping Shang^{1

2}, Ines Silva^{1

2}, Robyn P M Saw^{1

2

3}, Kerwin Shannon^{1

3

4}, John F Thompson^{1

2

3}, Nicholas K Hayward^{1

5}, Georgina V Long^{1

2

6}, Graham J Mann^{1

2

4}, Richard A Scolyer^{1

2

3}, James S Wilmott^{1

2}

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
² Sydney Medical School, The University of Sydney, Sydney, Australia.
³ Royal Prince Alfred Hospital, Sydney, Australia.
⁴ Centre for Cancer Research, Westmead Institute for Medical Research, Sydney, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ Royal North Shore Hospital, Sydney, Australia.

Abstract

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.

Keywords: SF3B1; hotspot mutation; mucosal melanoma; spliceosome; targeted sequencing.