title: Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma.
abstract: Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease.
authors.affiliation: aDepartment of Medicine, Division of Medical Oncology bDepartment of Pathology cDepartment of Surgery, School of Medicine dDepartment of Biostatistics and Informatics, Colorado School of Public Health eUniversity of Colorado Cancer Center fDepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Hintzsche
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Gorden
authors.forename: Carol M
authors.initials: CM
authors.lastname: Amato
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Wuensch
authors.forename: Steven E
authors.initials: SE
authors.lastname: Robinson
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Applegate
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Couts
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Medina
authors.forename: Keith R
authors.initials: KR
authors.lastname: Wells
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Wisell
authors.forename: Martin D
authors.initials: MD
authors.lastname: McCarter
authors.forename: Neil F
authors.initials: NF
authors.lastname: Box
authors.forename: Yiqun G
authors.initials: YG
authors.lastname: Shellman
authors.forename: Rene C
authors.initials: RC
authors.lastname: Gonzalez
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D025542:Neurofibromin 1; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D019009:Proto-Oncogene Proteins c-kit