Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.
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.
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
A Hunter
AH
Shain
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Maria
M
Garrido
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Thomas
T
Botton
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Eric
http://orcid.org/0000-0002-8106-0720
E
Talevich
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Iwei
I
Yeh
Five3 Genomics, LLC, Santa Cruz, California, USA.
J Zachary
JZ
Sanborn
Samsung Advanced Institute of Technology, Seoul, Korea.
Jongsuk
J
Chung
Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA.
Nicholas J
NJ
Wang
Melanoma Institute Australia, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Hojabr
H
Kakavand
Melanoma Institute Australia, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Graham J
GJ
Mann
Melanoma Institute Australia, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
John F
JF
Thompson
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Thomas
T
Wiesner
Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
Ritu
R
Roy
Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
Adam B
AB
Olshen
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Alexander
A
Gagnon
Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA.
Joe W
http://orcid.org/0000-0001-9225-6756
JW
Gray
Samsung Advanced Institute of Technology, Seoul, Korea.
Nam
N
Huh
Samsung Electronics Headquarters, Seoul, Korea.
Joe S
JS
Hur
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Klaus J
KJ
Busam
Melanoma Institute Australia, Sydney, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Richard A
RA
Scolyer
Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Raymond J
RJ
Cho
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Rajmohan
R
Murali
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.|Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
Boris C
BC
Bastian
D059472:Exome; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D020672:I-kappa B Proteins; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins