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J W. Harbour, Michael D. Onken, Lori A. Worley; Relationship Between GNAQ, GNA11 and BAP1 Mutations and Metastasis In Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5253.
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Three common mutations have now been described in uveal melanoma: GNAQ, GNA11 and BAP1. GNAQ and GNA11 mutations occur early in tumor progression, whereas BAP1 mutations appear to occur later and almost exclusively in metastasizing class 2 tumors. It has been speculated that GNA11 mutations are more strongly associated with metastasis and are more oncogenic than GNAQ mutations. The current study was designed to test this hypothesis by comparing the clinical features and outcomes of uveal melanomas with respect to their GNAQ, GNA11 and BAP1 mutation status.
Mutation status of GNAQ, GNA11 and BAP1, as well as gene expression profile (GEP) class were determined in 68 primary uveal melanomas. Statistical analysis was performed to identify significant associations between mutation status, GEP status, patient age, sex, ciliary body involvement, tumor diameter and thickness, scleral invasion and metastasis.
There was a strong association between metastasis and GEP class 2 (P < 0.0001), which in turn was strongly associated with the presence of BAP1 mutations (P < 10-6), but not with GNAQ mutations (P=0.6) or GNA11 mutations (P=0.8). There was no difference between GNAQ-mutant and GNA11-mutant tumors with respect to patient age (P=0.5), tumor diameter (P=0.9), scleral invasion (P=0.6) or metastasis (P = 0.8). GNA11 mutations were more likely to occur in ciliary body melanomas (P<0.01).
After adjusting statistically for ciliary body location, GNA11-mutant tumors were no more likely to metastasize than GNAQ-mutant tumors. BAP1 mutations were far more strongly associated with metastasis than either GNAQ or GNA11 mutations. A weak association between GNA11 mutations and metastasis noted in a previous study may be explained statistically by the tendency for GNA11 mutations to occur in ciliary body melanomas, which are known to have a higher metastatic rate than choroidal melanomas. These findings do not support GNA11 mutations leading to more aggressive tumors than GNAQ mutations. Further work is needed to understand why GNA11 mutations preferentially occur in ciliary body melanomas.
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