Exome sequencing identifies GRIN2A as frequently mutated in melanoma (original) (raw)

Nature Genetics volume 43, pages 442–446 (2011)Cite this article

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Abstract

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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References

  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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Acknowledgements

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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Author notes

  1. Vijay Walia and Jimmy C Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA
    Xiaomu Wei, Vijay Walia, Todd D Prickett, Jared Gartner & Yardena Samuels
  2. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA
    Jimmy C Lin
  3. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.,
    Jamie K Teer
  4. The Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA.,
    Sean Davis
  5. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Katherine Stemke-Hale & Michael A Davies
  6. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Michael A Davies
  7. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Jeffrey E Gershenwald
  8. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
    Jeffrey E Gershenwald
  9. Division of Medical Oncology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
    William Robinson & Steven Robinson
  10. The Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
    Steven A Rosenberg

Authors

  1. Xiaomu Wei
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  2. Vijay Walia
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  3. Jimmy C Lin
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  4. Jamie K Teer
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  5. Todd D Prickett
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  6. Jared Gartner
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  7. Sean Davis
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  8. Katherine Stemke-Hale
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  9. Michael A Davies
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  10. Jeffrey E Gershenwald
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  11. William Robinson
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  12. Steven Robinson
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  13. Steven A Rosenberg
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  14. Yardena Samuels
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NISC Comparative Sequencing Program

Contributions

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.

Corresponding author

Correspondence toYardena Samuels.

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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/ng.810

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