Oncogenic mutations in GNAQ occur early in uveal melanoma.
OBJECTIVE
Early/initiating oncogenic mutations have been identified for many cancers, but such mutations remain unidentified in uveal melanoma (UM). An extensive search for such mutations was undertaken, focusing on the RAF/MEK/ERK pathway, which is often the target of initiating mutations in other types of cancer.


METHODS
DNA samples from primary UMs were analyzed for mutations in 24 potential oncogenes that affect the RAF/MEK/ERK pathway. For GNAQ, a stimulatory alpha(q) G-protein subunit which was recently found to be mutated in UMs, resequencing was expanded to include 67 primary UMs and 22 peripheral blood samples. GNAQ status was analyzed for association with clinical, pathologic, chromosomal, immunohistochemical, and transcriptional features.


RESULTS
Activating mutations at codon 209 were identified in GNAQ in 33 (49%) of 67 primary UMs, including 2 (22%) of 9 iris melanomas and 31 (54%) of 58 posterior UMs. No mutations were found in the other 23 potential oncogenes. GNAQ mutations were not found in normal blood DNA samples. Consistent with GNAQ mutation being an early or initiating event, this mutation was not associated with any clinical, pathologic, or molecular features associated with late tumor progression.


CONCLUSIONS
GNAQ mutations occur in about half of UMs, representing the most common known oncogenic mutation in this cancer. The presence of this mutation in tumors at all stages of malignant progression suggests that it is an early event in UM. Mutations in this G-protein-coupled receptor provide new insights into UM pathogenesis and could lead to new therapeutic possibilities.
Onken
Michael D
MD
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Worley
Lori A
LA
Long
Meghan D
MD
Duan
Shenghui
S
Council
M Laurin
ML
Bowcock
Anne M
AM
Harbour
J William
JW
D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics*
D016326:Extracellular Matrix Proteins; D015513:Oncogene Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11