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Abstract
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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1 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
2 Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, Beijing, China
3 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
4 Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
5 Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
6 Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
7 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia
8 Dermatology Clinic, University Hospital Zürich, University of Zurich, Zurich, Switzerland
9 Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden
10 Departments of Dermatology and Pathology and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA
11 Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA
12 Department of Pathology, University of California, San Francisco, CA, USA
13 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
14 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia
15 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia