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

Newell, Felicity ; Kong, Yan ; Wilmott, James S. ; Johansson, Peter A. ; Ferguson, Peter M. ; Cui, Chuanliang ; Li, Zhongwu ; Kazakoff, Stephen H. ; Burke, Hazel and Dodds, Tristan J. , et al. (2019) In Nature Communications 10(1).
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... (More)

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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Nature Communications
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10
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1
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3163
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Nature Publishing Group
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  • scopus:85069434507
ISSN
2041-1723
DOI
10.1038/s41467-019-11107-x
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English
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e8a99511-b6da-408e-9275-3099f7c069a2
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2019-08-02 10:38:40
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2020-02-19 05:37:24
@article{e8a99511-b6da-408e-9275-3099f7c069a2,
  abstract     = {<p>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.</p>},
  author       = {Newell, Felicity and Kong, Yan and Wilmott, James S. and Johansson, Peter A. and Ferguson, Peter M. and Cui, Chuanliang and Li, Zhongwu and Kazakoff, Stephen H. and Burke, Hazel and Dodds, Tristan J. and Patch, Ann Marie and Nones, Katia and Tembe, Varsha and Shang, Ping and van der Weyden, Louise and Wong, Kim and Holmes, Oliver and Lo, Serigne and Leonard, Conrad and Wood, Scott and Xu, Qinying and Rawson, Robert V. and Mukhopadhyay, Pamela and Dummer, Reinhard and Levesque, Mitchell P. and Jönsson, Göran and Wang, Xuan and Yeh, Iwei and Wu, Hong and Joseph, Nancy and Bastian, Boris C. and Long, Georgina V. and Spillane, Andrew J. and Shannon, Kerwin F. and Thompson, John F. and Saw, Robyn P.M. and Adams, David J. and Si, Lu and Pearson, John V. and Hayward, Nicholas K. and Waddell, Nicola and Mann, Graham J. and Guo, Jun and Scolyer, Richard A.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets},
  url          = {http://dx.doi.org/10.1038/s41467-019-11107-x},
  doi          = {10.1038/s41467-019-11107-x},
  volume       = {10},
  year         = {2019},
}