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Exome sequencing identifies GRIN2A as frequently mutated in melanoma

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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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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NCBI Reference Sequence

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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

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  1. Xiaomu Wei
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Consortia

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

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