Oncogenic mutations in GNAQ occur early in uveal melanoma

Michael D. Onken, Lori A. Worley, Meghan D. Long, Shenghui Duan, M. Laurin Council, Anne M. Bowcock, J. William Harbour

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

PURPOSE. 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 αq 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.

Original languageEnglish
Pages (from-to)5230-5234
Number of pages5
JournalInvestigative Ophthalmology and Visual Science
Volume49
Issue number12
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

Fingerprint

Mutation
MAP Kinase Signaling System
Neoplasms
Uveal melanoma
Oncogenes
DNA
Protein Subunits
Iris
G-Protein-Coupled Receptors
GTP-Binding Proteins
Codon
Melanoma

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Onken, M. D., Worley, L. A., Long, M. D., Duan, S., Council, M. L., Bowcock, A. M., & William Harbour, J. (2008). Oncogenic mutations in GNAQ occur early in uveal melanoma. Investigative Ophthalmology and Visual Science, 49(12), 5230-5234. https://doi.org/10.1167/iovs.08-2145

Oncogenic mutations in GNAQ occur early in uveal melanoma. / Onken, Michael D.; Worley, Lori A.; Long, Meghan D.; Duan, Shenghui; Council, M. Laurin; Bowcock, Anne M.; William Harbour, J.

In: Investigative Ophthalmology and Visual Science, Vol. 49, No. 12, 01.12.2008, p. 5230-5234.

Research output: Contribution to journalArticle

Onken, MD, Worley, LA, Long, MD, Duan, S, Council, ML, Bowcock, AM & William Harbour, J 2008, 'Oncogenic mutations in GNAQ occur early in uveal melanoma', Investigative Ophthalmology and Visual Science, vol. 49, no. 12, pp. 5230-5234. https://doi.org/10.1167/iovs.08-2145
Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Investigative Ophthalmology and Visual Science. 2008 Dec 1;49(12):5230-5234. https://doi.org/10.1167/iovs.08-2145
Onken, Michael D. ; Worley, Lori A. ; Long, Meghan D. ; Duan, Shenghui ; Council, M. Laurin ; Bowcock, Anne M. ; William Harbour, J. / Oncogenic mutations in GNAQ occur early in uveal melanoma. In: Investigative Ophthalmology and Visual Science. 2008 ; Vol. 49, No. 12. pp. 5230-5234.
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abstract = "PURPOSE. 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 αq 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.",
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AU - Onken, Michael D.

AU - Worley, Lori A.

AU - Long, Meghan D.

AU - Duan, Shenghui

AU - Council, M. Laurin

AU - Bowcock, Anne M.

AU - William Harbour, J.

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N2 - PURPOSE. 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 αq 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.

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