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Nat Genet. 2015 Oct;47(10):1194-9. doi: 10.1038/ng.3382. Epub 2015 Sep 7.

Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.

Shain AH1,2,3, Garrido M1,2,3, Botton T1,2,3, Talevich E1,2,3, Yeh I1,2,3, Sanborn JZ4, Chung J5, Wang NJ6,7, Kakavand H8,9, Mann GJ8,9, Thompson JF8,9,10, Wiesner T11, Roy R2, Olshen AB2,12, Gagnon A1,2,3, Gray JW6,7, Huh N5, Hur JS13, Busam KJ14, Scolyer RA8,9,10, Cho RJ3, Murali R14,15, Bastian BC1,2,3.

Author information

  • 1Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
  • 2Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
  • 3Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
  • 4Five3 Genomics, LLC, Santa Cruz, California, USA.
  • 5Samsung Advanced Institute of Technology, Seoul, Korea.
  • 6Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA.
  • 7Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA.
  • 8Melanoma Institute Australia, Sydney, New South Wales, Australia.
  • 9Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
  • 10Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
  • 11Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 12Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
  • 13Samsung Electronics Headquarters, Seoul, Korea.
  • 14Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 15Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Abstract

Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes in a validation cohort of 42 cases. A high mutation burden (median of 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen, indicating a superficially located cell of origin. Newly identified alterations included recurrent promoter mutations of NFKBIE, encoding NF-κB inhibitor ɛ (IκBɛ), in 14.5% of samples. Common oncogenic mutations in melanomas, in particular in BRAF (encoding p.Val600Glu) and NRAS (encoding p.Gln61Lys or p.Gln61Arg), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3CA, some of which are candidates for targeted therapies.

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PMID:
26343386
PMCID:
PMC4589486
DOI:
10.1038/ng.3382
[PubMed - indexed for MEDLINE]
Free PMC Article
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