Exome sequencing identifies GRIN2A as frequently mutated in melanoma

• Published in: Nature genetics Vol. 43; no. 5; pp. 442 - 446
• Main Authors: XIAOMU WEI, WALIA, Vijay, GERSHENWALD, Jeffrey E, ROBINSON, William, ROBINSON, Steven, ROSENBERG, Steven A, SAMUELS, Yardena, LIN, Jimmy C, TEER, Jamie K, PRICKETT, Todd D, GARTNER, Jared, DAVIS, Sean, PROGRAM, Nisc Comparative Sequencing, STEMKE-HALE, Katherine, DAVIES, Michael A
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.05.2011
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Cloning; Dermatology; DNA Primers - genetics; DNA sequencing; Exons; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Glutamic Acid - metabolism; Health aspects; Humans; Medical sciences; Melanoma; Melanoma - genetics; Melanoma - metabolism; Molecular Sequence Data; Mutation; Nuclear Proteins - genetics; Nucleotide sequencing; Oncogenes; Proteins; Receptors, N-Methyl-D-Aspartate - genetics; Risk factors; Sequence Homology, Amino Acid; Signal Transduction; Studies; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; United States; Identification; Malignant tumor; Sequencing; Malignant melanoma; Cancer
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.810

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.