Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

Felicity Newell, Yan Kong, James S. Wilmott, Peter A. Johansson, Peter M. Ferguson, Chuanliang Cui, Zhongwu Li, Stephen H. Kazakoff, Hazel Burke, Tristan J. Dodds, Ann-Marie Patch, Katia Nones, Varsha Tembe, Ping Shang, Louise van der Weyden, Kim Wong, Oliver Holmes, Serigne Lo, Conrad Leonard, Scott Wood, Qinying Xu, Robert V. Rawson, Pamela Mukhopadhyay, Reinhard Dummer, Mitchell P. Levesque, Göran Jönsson, Xuan Wang, Iwei Yeh, Hong Wu, Nancy Joseph, Boris C. Bastian, Georgina V. Long, Andrew J. Spillane, Kerwin F. Shannon, John F. Thompson, Robyn P. M. Saw, David J. Adams, Lu Si, John V. Pearson, Nicholas K. Hayward, Nicola Waddell, Graham J. Mann, Jun Guo and Richard A. Scolyer ()
Additional contact information
Felicity Newell: QIMR Berghofer Medical Research Institute
Yan Kong: Peking University Cancer Hospital & Institute
James S. Wilmott: The University of Sydney
Peter A. Johansson: QIMR Berghofer Medical Research Institute
Peter M. Ferguson: The University of Sydney
Chuanliang Cui: Peking University Cancer Hospital & Institute
Zhongwu Li: Peking University Cancer Hospital & Institute
Stephen H. Kazakoff: QIMR Berghofer Medical Research Institute
Hazel Burke: The University of Sydney
Tristan J. Dodds: The University of Sydney
Ann-Marie Patch: QIMR Berghofer Medical Research Institute
Katia Nones: QIMR Berghofer Medical Research Institute
Varsha Tembe: The University of Sydney
Ping Shang: The University of Sydney
Louise van der Weyden: Wellcome Trust Sanger Institute, Hinxton
Kim Wong: Wellcome Trust Sanger Institute, Hinxton
Oliver Holmes: QIMR Berghofer Medical Research Institute
Serigne Lo: The University of Sydney
Conrad Leonard: QIMR Berghofer Medical Research Institute
Scott Wood: QIMR Berghofer Medical Research Institute
Qinying Xu: QIMR Berghofer Medical Research Institute
Robert V. Rawson: The University of Sydney
Pamela Mukhopadhyay: QIMR Berghofer Medical Research Institute
Reinhard Dummer: University Hospital Zürich, University of Zurich
Mitchell P. Levesque: University Hospital Zürich, University of Zurich
Göran Jönsson: Lund University
Xuan Wang: Peking University Cancer Hospital & Institute
Iwei Yeh: University of California, San Francisco (UCSF)
Hong Wu: Fox Chase Cancer Center
Nancy Joseph: University of California
Boris C. Bastian: University of California, San Francisco (UCSF)
Georgina V. Long: The University of Sydney
Andrew J. Spillane: The University of Sydney
Kerwin F. Shannon: The University of Sydney
John F. Thompson: The University of Sydney
Robyn P. M. Saw: The University of Sydney
David J. Adams: Wellcome Trust Sanger Institute, Hinxton
Lu Si: Peking University Cancer Hospital & Institute
John V. Pearson: QIMR Berghofer Medical Research Institute
Nicholas K. Hayward: QIMR Berghofer Medical Research Institute
Nicola Waddell: QIMR Berghofer Medical Research Institute
Graham J. Mann: The University of Sydney
Jun Guo: Peking University Cancer Hospital & Institute
Richard A. Scolyer: The University of Sydney

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11107-x

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