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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

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

Comment in

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

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