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Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3



Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis1,2,3. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis2. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625.

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Figure 1: Exome sequencing of uveal melanomas.
Figure 2: Results of targeted resequencing.
Figure 3: Alignment of EIF1AX amino acid sequences from 19 uveal melanomas with an EIF1AX mutation.

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We thank M. Klutz and D. Falkenstein for technical assistance and H.-J. Lüdecke for elaborate discussion. This work was supported by the Deutsche Krebshilfe (DKF, 108612), the Mercator Research Center Ruhr (Pr-2010-0016) and the Wilhelm Sander Stiftung (2012.006.1) and by the Intramural Research Program of the US National Institutes of Health.

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Authors and Affiliations



M.Z. designed and supervised the study, and wrote the manuscript. C.M. and N.B. provided the samples and clinical data of the affected individuals. J.v.d.N. performed immunohistochemistry. L.K.-H. performed next-generation sequencing. M.M. and S.R. performed bioinformatic analysis of exome sequencing data. L.M. performed exome capture of tumor and blood samples. C.M. and P.T. performed Sanger resequencing and analysis of the sequencing data. B.H. and D.R.L. participated in the design of the study and revised the manuscript. D.R.L. performed statistical analysis. A.G.H. provided background on eIF1A function.

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Correspondence to Michael Zeschnigk.

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Martin, M., Maßhöfer, L., Temming, P. et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet 45, 933–936 (2013).

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