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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 pathogenesis1,2,3. 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 cancers4. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen5, 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.

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Figure 1: Desmoplastic melanomas have a substantial point mutation burden consistent with UV radiation–induced damage.
Figure 2: Nomination of driver mutations in desmoplastic melanoma.
Figure 3: Genetic alterations of CBL, MAP3K1, FBXW7 and NFKBIE.
Figure 4: Recurrent mutations affect the promoter of NFKBIE.
Figure 5: The mutational landscape of desmoplastic melanoma.

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This work was supported by US National Institutes of Health grants R01 CA131524 (B.C.B.), P01 CA025874 (B.C.B.), P30 CA82103 (A.B.O.) and 5T32 CA177555-02 (A.H.S.), the American Skin Association (B.C.B.), the Gerson and Barbara Bakar Distinguished Chair in Cancer Biology (B.C.B.), the Well Aging Research Center at the Samsung Advanced Institute of Technology under the auspices of S.C. Park, the Dermatology Foundation and US National Institutes of Health grants K08 CA169865 (R.J.C.), U54 CA112970 (J.W.G.) and the Oregon Health and Sciences University Knight Cancer Institute 5P30 CA069533 (J.W.G.). The authors acknowledge support from the Australian National Health and Medical Research Council, Cancer Institute New South Wales, the Melanoma Foundation of the University of Sydney and the staff of Melanoma Institute Australia and Royal Prince Alfred Hospital. Finally, we would like to thank A. Ribas (UCLA Jonsson Comprehensive Cancer Center) and G. Long (Melanoma Institute Australia) for providing samples used in this study.

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Authors and Affiliations



A.H.S., R.M. and B.C.B. designed the study. M.G., I.Y., H.K., G.J.M., J.F.T., T.W., K.J.B., R.A.S., R.M. and B.C.B. provided cases. A.H.S., M.G., I.Y., K.J.B., R.A.S., R.M. and B.C.B. evaluated and/or microdissected cases. J.C., N.J.W., A.G., J.W.G., N.H., J.S.H., R.J.C. and B.C.B. sequenced samples. A.H.S., M.G., R.R., A.B.O., E.T. and B.C.B. analyzed copy number data. A.H.S., J.Z.S., R.J.C. and B.C.B. analyzed sequencing data. A.H.S. and R.M. carried out immunohistochemistry. A.H.S. and T.B. performed Sanger sequencing, RT-PCR, immunoblots and cell culture work. A.H.S. and B.C.B. wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Boris C Bastian.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11. (PDF 10459 kb)

Supplementary Table 1: Sample descriptions. (XLSX 35 kb)

Supplementary Table 2: Target intervals.

The 293 genes included in the validation cohort are listed in tab 1. The second tab describes the actual genomic intervals tiled. (XLSX 400 kb)

Supplementary Table 3: Discovery mutations. (XLSX 2685 kb)

Supplementary Table 4: Validation mutations. (XLSX 388 kb)

Supplementary Table 5: NFKBIE mutation details. (XLSX 50 kb)

Supplementary Table 6: Copy number circular binary segmentation (CBS) calls.

CBS calls generated from the higher-resolution primary copy number platform (Supplementary Table 1) are listed in the first tab. For many samples, copy number was also inferred using an orthogonal assay, and those copy number calls are listed in the second tab. Copy number data agreed very well between the two platforms. (XLSX 1141 kb)

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Shain, A., Garrido, M., Botton, T. et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat Genet 47, 1194–1199 (2015).

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