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.

Details

Title
Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
Author
Newell, Felicity 1 ; Kong, Yan 2 ; Wilmott, James S 3 ; Johansson, Peter A 1 ; Ferguson, Peter M 3   VIAFID ORCID Logo  ; Cui, Chuanliang 2 ; Li, Zhongwu 2 ; Kazakoff, Stephen H 1 ; Burke, Hazel 4 ; Dodds, Tristan J 3 ; Patch, Ann-Marie 1   VIAFID ORCID Logo  ; Nones, Katia 1 ; Tembe, Varsha 5 ; Shang, Ping 4 ; van der Weyden, Louise 6 ; Wong, Kim 6   VIAFID ORCID Logo  ; Holmes, Oliver 1 ; Lo, Serigne 3   VIAFID ORCID Logo  ; Conrad, Leonard 1 ; Wood, Scott 1 ; Xu, Qinying 1 ; Rawson, Robert V 7 ; Mukhopadhyay, Pamela 1 ; Dummer, Reinhard 8 ; Levesque, Mitchell P 8 ; Jönsson, Göran 9 ; Wang, Xuan 2 ; Yeh, Iwei 10 ; Wu, Hong 11 ; Joseph, Nancy 12 ; Bastian, Boris C 10   VIAFID ORCID Logo  ; Long, Georgina V 13 ; Spillane, Andrew J 3 ; Shannon, Kerwin F 3 ; Thompson, John F 14   VIAFID ORCID Logo  ; Saw, Robyn P M 3 ; Adams, David J 6 ; Lu, Si 2 ; Pearson, John V 1 ; Hayward, Nicholas K 1 ; Waddell, Nicola 1 ; Mann, Graham J 15 ; Guo, Jun 2 ; Scolyer, Richard A 14   VIAFID ORCID Logo 

 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 
 Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, Beijing, China 
 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia 
 Sydney Medical School, The University of Sydney, Sydney, NSW, Australia 
 Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia 
 Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK 
 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia 
 Dermatology Clinic, University Hospital Zürich, University of Zurich, Zurich, Switzerland 
 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 
Pages
1-15
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2260059359
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.