Prognostic Values of G-Protein Mutations in Metastatic Uveal Melanoma

SIMPLE SUMMARY: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. More than 90% of UMs harbor mutually exclusive activating mutations in G-proteins. The mutations are early events in UM development and considered to be driver mutations in carcinogenesis. Even after treatment of primary uveal melanoma, up to 50% of patients subsequently develop recurrence, predominantly in the liver. GNAQ mutations are not reported to be correlated to survival, while the mutations in GNA11 are reported more frequently in metastatic UM. We investigated the correlation of survival after development of metastasis (Met-to-Death) of metastatic uveal melanoma (MUM) patients with GNA11 and GNAQ mutations. We identified that MUM with mutation patterns of Q209P vs. Q209L in GNA11 and GNAQ might predict survival of MUM patients. ABSTRACT: Uveal melanoma is the most common primary ocular malignancy in adults, characterized by gene mutations in G protein subunit alpha q (GNAQ) and G protein subunit alpha 11 (GNA11). Although they are considered to be driver mutations, their role in MUM remains elusive. We investigated key somatic mutations of MUM and their impact on patients’ survival after development of systemic metastasis (Met-to-Death). Metastatic lesions from 87 MUM patients were analyzed by next generation sequencing (NGS). GNA11 (41/87) and GNAQ (39/87) mutations were most predominantly seen in MUM. Most GNA11 mutations were Q209L (36/41), whereas GNAQ mutations comprised Q209L (14/39) and Q209P (21/39). Epigenetic pathway mutations BAP1 (42/66), SF3B1 (11/66), FBXW7 (2/87), PBRM1 (1/66), and SETD2 (1/66) were found. No specimen had the EIF1AX mutation. Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated.