title: Exome sequencing identifies GRIN2A as frequently mutated in melanoma.
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.
authors.affiliation: The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.forename: Vijay
authors.initials: V
authors.lastname: Walia
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.forename: Jared
authors.initials: J
authors.lastname: Gartner
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.forename: Steven
authors.initials: S
authors.lastname: Robinson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D055106:Genome-Wide Association Study; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D009857:Oncogenes; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D018698:Glutamic Acid; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C113829:transformation-transcription domain-associated protein