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Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma

Hintzsche, Jennifer D.a; Gorden, Nicholas T.a; Amato, Carol M.a; Kim, Jihyea,e; Wuensch, Kelsey E.a; Robinson, Steven E.a; Applegate, Allison J.a; Couts, Kasey L.a; Medina, Theresa M.a; Wells, Keith R.a; Wisell, Joshua A.b,e; McCarter, Martin D.c,e; Box, Neil F.e,f; Shellman, Yiqun G.f; Gonzalez, Rene C.a,e; Lewis, Karl D.a,e; Tentler, John J.a,e; Tan, Aik Choona,d,e; Robinson, William A.a,e

doi: 10.1097/CMR.0000000000000345

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.

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

Correspondence to William A. Robinson, MD, PhD, Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Tel: +1 303 724 3870; fax: +1 303 724 3889; e-mail:

Correspondence to Aik Choon Tan, PhD, Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Tel: +1 303 724 2520; fax: +1 303 724 3889; e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received November 16, 2016

Accepted January 20, 2017

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