title: Mutations in GNA11 in uveal melanoma.
abstract: BACKGROUND
  Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas.
  
  
  METHODS
  We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi.
  
  
  RESULTS
  We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway.
  
  
  CONCLUSIONS
  Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Van Raamsdonk
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Griewank
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Crosby
authors.forename: Maria C
authors.initials: MC
authors.lastname: Garrido
authors.forename: Swapna
authors.initials: S
authors.lastname: Vemula
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.forename: Werner
authors.initials: W
authors.lastname: Wackernagel
authors.forename: Gary
authors.initials: G
authors.lastname: Green
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.forename: M Mert
authors.initials: MM
authors.lastname: Sozen
authors.forename: Gail
authors.initials: G
authors.lastname: Baimukanova
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.forename: Joan
authors.initials: J
authors.lastname: O'Brien
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D008544:Melanocytes; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009506:Nevus / Q000235:genetics / Q000401:mortality; D018329:Nevus, Blue / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000235:genetics* / Q000401:mortality
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11