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Exome sequencing identifies GRIN2A as frequently mutated in melanoma


The incidence of melanoma is increasing more than any other cancer, and knowledge of its genetic alterations is limited. To systematically analyze such alterations, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. Using stringent criteria, we identified 68 genes that appeared to be somatically mutated at elevated frequency, many of which are not known to be genetically altered in tumors. Most importantly, we discovered that TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (4%), as well as a previously unidentified gene, GRIN2A, which was mutated in 33% of melanoma samples. The nature, pattern and functional evaluation of the TRRAP recurrent mutation suggest that TRRAP functions as an oncogene. Our study provides, to our knowledge, the most comprehensive map of genetic alterations in melanoma to date and suggests that the glutamate signaling pathway is involved in this disease.

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Figure 1: Distribution of new non-synonymous recurrent mutations.
Figure 2: Effect of mutant TRRAP on colony formation and apoptosis.
Figure 3: Location of somatic mutations in GRIN2A.

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  1. Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010).

    Article  Google Scholar 

  2. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  CAS  Google Scholar 

  3. Curtin, J.A., Busam, K., Pinkel, D. & Bastian, B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 24, 4340–4346 (2006).

    Article  CAS  Google Scholar 

  4. Prickett, T.D. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat. Genet. 41, 1127–1132 (2009).

    Article  CAS  Google Scholar 

  5. Pleasance, E.D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).

    Article  CAS  Google Scholar 

  6. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182–189 (2009).

    Article  CAS  Google Scholar 

  7. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  8. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  Google Scholar 

  9. Bos, J.L. et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 327, 293–297 (1987).

    Article  CAS  Google Scholar 

  10. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  Google Scholar 

  11. McMahon, S.B., Van Buskirk, H.A., Dugan, K.A., Copeland, T.D. & Cole, M.D. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94, 363–374 (1998).

    Article  CAS  Google Scholar 

  12. Barlev, N.A. et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol. Cell 8, 1243–1254 (2001).

    Article  CAS  Google Scholar 

  13. Herceg, Z. et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat. Genet. 29, 206–211 (2001).

    Article  CAS  Google Scholar 

  14. Johnson, J.W. & Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–531 (1987).

    Article  CAS  Google Scholar 

  15. Vogelstein, B. & Kinzler, K.W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).

    Article  CAS  Google Scholar 

  16. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    Article  CAS  Google Scholar 

  17. Pin, J.P., Gomeza, J., Joly, C. & Bockaert, J. The metabotropic glutamate receptors: their second intracellular loop plays a critical role in the G-protein coupling specificity. Biochem. Soc. Trans. 23, 91–96 (1995).

    Article  CAS  Google Scholar 

  18. Anton, E.S. et al. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat. Neurosci. 7, 1319–1328 (2004).

    Article  CAS  Google Scholar 

  19. Rieff, H.I. et al. Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J. Neurosci. 19, 10757–10766 (1999).

    Article  CAS  Google Scholar 

  20. Ozaki, M., Sasner, M., Yano, R., Lu, H.S. & Buonanno, A. Neuregulin-β induces expression of an NMDA-receptor subunit. Nature 390, 691–694 (1997).

    Article  CAS  Google Scholar 

  21. Dalva, M.B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).

    Article  CAS  Google Scholar 

  22. Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001).

    Article  CAS  Google Scholar 

  23. Pollock, P.M. et al. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat. Genet. 34, 108–112 (2003).

    Article  CAS  Google Scholar 

  24. Shin, S.S. et al. Oncogenic activities of metabotropic glutamate receptor 1 (Grm1) in melanocyte transformation. Pigment Cell Melanoma Res. 21, 368–378 (2008).

    Article  CAS  Google Scholar 

  25. Rzeski, W., Turski, L. & Ikonomidou, C. Glutamate antagonists limit tumor growth. Proc. Natl. Acad. Sci. USA 98, 6372–6377 (2001).

    Article  CAS  Google Scholar 

  26. Palavalli, L.H. et al. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat. Genet. 41, 518–520 (2009).

    Article  CAS  Google Scholar 

  27. Morente, M.M. et al. TuBaFrost 2: standardising tissue collection and quality control procedures for a European virtual frozen tissue bank network. Eur. J. Cancer 42, 2684–2691 (2006).

    Article  CAS  Google Scholar 

  28. Davies, M.A. et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin. Cancer Res. 15, 7538–7546 (2009).

    Article  CAS  Google Scholar 

  29. Teer, J.K. et al. Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res. 20, 1420–1431 (2010).

    Article  CAS  Google Scholar 

  30. Biesecker, L.G. et al. The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res. 19, 1665–1674 (2009).

    Article  CAS  Google Scholar 

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We thank V. Maduro, H. Abaan, P. Cruz and J. Mullikin for generating the sequence data analyzed here. We thank V.G. Prieto for pathologic review of the biospecimens from MelCore at MD Anderson. We thank T. Wolfsberg for bioinformatics help and J. Fekecs and D. Leja for graphical assistance. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, National Institutes of Health, USA and The University of Texas MD Anderson Cancer Center Melanoma SPORE (P50 CA93459).

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Authors and Affiliations




X.W., V.W., J.C.L., J.K.T., T.D.P. and Y.S. designed the study; K.S.-H., M.A.D., J.E.G., W.R., S.R. and S.A.R. collected and analyzed the melanoma samples; X.W., J.K.T., J.G., J.C.L., S.D. and the NISC Comparative Sequencing Program analyzed the genetic data; V.W. and T.D.P. performed and analyzed the functional data. All authors contributed to the final version of the paper.

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Correspondence to Yardena Samuels.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 4–9 and Supplementary Note. (PDF 938 kb)

Supplementary Table 1

Score cutoff for determination of melanoma somatic mutations (XLS 39 kb)

Supplementary Table 2

Somatic mutations identified in the Discovery Screen (XLS 1087 kb)

Supplementary Table 3

Significance of the observed mutation rate over the expected mutation rate (XLS 407 kb)

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Wei, X., Walia, V., Lin, J. et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet 43, 442–446 (2011).

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