期刊
NATURE GENETICS
卷 47, 期 10, 页码 1194-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3382
关键词
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资金
- US National Institutes of Health [R01 CA131524, P01 CA025874, P30 CA82103, 5T32 CA17755502, K08 CA169865, U54 CA112970]
- American Skin Association
- Gerson and Barbara Bakar Distinguished Chair in Cancer Biology
- Well Aging Research Center at the Samsung Advanced Institute of Technology under S.C. Park
- Dermatology Foundation
- Oregon Health and Sciences University Knight Cancer Institute [5P30 CA069533]
- Australian National Health and Medical Research Council
- Cancer Institute New South Wales
- Melanoma Foundation of the University of Sydney
- Royal Prince Alfred Hospital
Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis1-3. 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(4). Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen(5), indicating a superficially located cell of origin. Newly identified alterations included recurrent promoter mutations of NFKBIE, encoding NF-kappa B inhibitor. (I kappa B epsilon), 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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