Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway Journal Article
| Authors: | Shain, A. H.; Garrido, M.; Botton, T.; Talevich, E.; Yeh, I.; Sanborn, J. Z.; Chung, J.; Wang, N. J.; Kakavand, H.; Mann, G. J.; Thompson, J. F.; Wiesner, T.; Roy, R.; Olshen, A. B.; Gagnon, A.; Gray, J. W.; Huh, N.; Hur, J. S.; Busam, K. J.; Scolyer, R. A.; Cho, R. J.; Murali, R.; Bastian, B. C. |
| Article Title: | Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway |
| 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. © 2015 Nature America, Inc. |
| Keywords: | immunohistochemistry; signal transduction; mitogen activated protein kinase; clinical article; gene mutation; promoter region; drug targeting; gene; melanoma; epidermal growth factor receptor; cohort analysis; immunoglobulin enhancer binding protein; enzyme activity; phosphatidylinositol 3 kinase; oncogene; desmoplastic melanoma; exome; human; priority journal; article; nfkbie gene |
| Journal Title: | Nature Genetics |
| Volume: | 47 |
| Issue: | 10 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-10-01 |
| Start Page: | 1194 |
| End Page: | 1199 |
| Language: | English |
| DOI: | 10.1038/ng.3382 |
| PROVIDER: | scopus |
| PMCID: | PMC4589486 |
| PUBMED: | 26343386 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work