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

A. Hunter Shain, Maria Garrido, Thomas Botton, Eric Talevich, Iwei Yeh, J. Zachary Sanborn, Jongsuk Chung, Nicholas J. Wang, Hojabr Kakavand, Graham J. Mann, John F. Thompson, Thomas Wiesner, Ritu Roy, Adam B. Olshen, Alexander Gagnon, Joe Gray, Nam Huh, Joe S. Hur, Klaus J. Busam, Richard A. ScolyerRaymond J. Cho, Rajmohan Murali, Boris C. Bastian

Research output: Contribution to journalArticle

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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 ε (IκBε), 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.

Original languageEnglish (US)
Pages (from-to)1194-1199
Number of pages6
JournalNature Genetics
Volume47
Issue number10
DOIs
StatePublished - Sep 29 2015

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Exome
Melanoma
Mutation
Mutagens
Phosphatidylinositol 3-Kinases
Histology
Genome
Radiation
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Shain, A. H., Garrido, M., Botton, T., Talevich, E., Yeh, I., Sanborn, J. Z., ... Bastian, B. C. (2015). Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nature Genetics, 47(10), 1194-1199. https://doi.org/10.1038/ng.3382

Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. / Shain, A. Hunter; Garrido, Maria; Botton, Thomas; Talevich, Eric; Yeh, Iwei; Sanborn, J. Zachary; Chung, Jongsuk; Wang, Nicholas J.; Kakavand, Hojabr; Mann, Graham J.; Thompson, John F.; Wiesner, Thomas; Roy, Ritu; Olshen, Adam B.; Gagnon, Alexander; Gray, Joe; Huh, Nam; Hur, Joe S.; Busam, Klaus J.; Scolyer, Richard A.; Cho, Raymond J.; Murali, Rajmohan; Bastian, Boris C.

In: Nature Genetics, Vol. 47, No. 10, 29.09.2015, p. 1194-1199.

Research output: Contribution to journalArticle

Shain, AH, Garrido, M, Botton, T, Talevich, E, Yeh, I, Sanborn, JZ, Chung, J, Wang, NJ, Kakavand, H, Mann, GJ, Thompson, JF, Wiesner, T, Roy, R, Olshen, AB, Gagnon, A, Gray, J, Huh, N, Hur, JS, Busam, KJ, Scolyer, RA, Cho, RJ, Murali, R & Bastian, BC 2015, 'Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway', Nature Genetics, vol. 47, no. 10, pp. 1194-1199. https://doi.org/10.1038/ng.3382
Shain, A. Hunter ; Garrido, Maria ; Botton, Thomas ; Talevich, Eric ; Yeh, Iwei ; Sanborn, J. Zachary ; Chung, Jongsuk ; Wang, Nicholas J. ; Kakavand, Hojabr ; Mann, Graham J. ; Thompson, John F. ; Wiesner, Thomas ; Roy, Ritu ; Olshen, Adam B. ; Gagnon, Alexander ; Gray, Joe ; Huh, Nam ; Hur, Joe S. ; Busam, Klaus J. ; Scolyer, Richard A. ; Cho, Raymond J. ; Murali, Rajmohan ; Bastian, Boris C. / Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. In: Nature Genetics. 2015 ; Vol. 47, No. 10. pp. 1194-1199.
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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 ε (IκBε), 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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N2 - 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 ε (IκBε), 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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