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

Felicity Newell(QIMR Berghofer Medical Research Institute), Yan Kong(Peking University), 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), Zhongwu Li(Peking University), 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), Kátia Nones(QIMR Berghofer Medical Research Institute), Varsha Tembe(The University of Sydney), Ping Shang(The University of Sydney), Louise van der Weyden(Wellcome Sanger Institute), Kim Wong(Wellcome Sanger Institute), 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 of Zurich), Mitchell P. Levesque(University of Zurich), Göran Jönsson(Lund University), Xuan Wang(Peking University), Iwei Yeh(University of California, San Francisco), Hong Wu(Fox Chase Cancer Center), Nancy M. Joseph(University of California, San Francisco), Boris C. Bastian(University of California, San Francisco), 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 Sanger Institute), Lu Si(Peking University), 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), Richard A. Scolyer(The University of Sydney)
Nature Communications
July 18, 2019
10.1038/s41467-019-11107-x
Cited by 336Open Access
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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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