Abstract Uveal melanoma is the most common ocular tumor in adults. It harbors genetic mutations very different from those seen in cutaneous melanoma. Liver metastasis is common in uveal melanoma and contributes to the very poor prognosis with average survival of several months. Currently there is no treatment for metastatic uveal melanoma. Activating mutations in GNAQ and GNA11 are the most important cancer drivers, as approximately 80% of uveal melanomas have mutations in either GNAQ or GNA11. Our recent studies have shown that the mutant GNAQ/11 potently activates the YAP oncoprotein, which is a key component of the Hippo tumor suppressor pathway. Moreover, the elevated YAP activity is essential for tumor growth of uveal melanoma cells containing an activating mutation in GNAQ/11. Besides GNAQ/11, mutations in BAP1, SF3B1, and EIF1AX are also frequently observed in uveal melanoma in a mutually exclusive manner. However, a mechanistic understanding of these genes in uveal melanoma and their functional interactions are largely unknown. The major goals of this project are to determine the contributions of the genes commonly mutated in uveal melanoma and their functional interaction in promoting tumorigenesis of uveal melanoma. We also aim to characterize and validate potential therapeutic targets and tools for treatment of uveal melanoma.

Narrative Cancer genetic analyses have revealed the major genes, including GNAQ, GNA11, BAP1, EIF1AX, and SF3B1, associated with ocular melanoma. We have observed that dysregulation of the Hippo tumor suppressor pathway by constitutively active mutations in GNAQ/11 plays a critical role in ocular melanoma tumorigenesis. The major goals of this proposal are to understand the functional interaction of genes mutated in ocular melanoma and identify therapeutic avenues for this deadly ocular cancer.