Allele-Specific GNAQ Q209 Mutations Reveal Context-Dependent Oncogenic Programs in Uveal Melanoma

Uveal melanoma (UM) is driven by activating GNAQ/GNA11 mutations, predominantly at the hotspot Q209 residue. However, the functional impact of distinct GNAQ Q209 substitutions on downstream signaling and malignant progression remains unclear. Using immune-competent, multistep UM mouse models combining eye-restricted mutant GNAQ with BAP1 loss and MYC activation, we directly compared GNAQ^Q209L and GNAQ^Q209R in an otherwise matched genetic context. Tumors arising from either allele shared similar histology and cell-state composition. However, GNAQ^Q209L tumors progressed faster and were associated with reduced survival. In contrast, GNAQ^Q209R tumor-derived cell lines exhibited greater ex vivo fitness (proliferation, clonogenicity, and migration), whereas GNAQ^Q209L-derived lines were relatively fragile in 2D culture. At the molecular level, GNAQ^Q209R tumors preferentially engaged the FAK-YAP axis in primary lesions and derived cell lines. Together, these results support an allele-dependent, context-specific trade-off in which higher output GNAQ^Q209L favors rapid in vivo expansion, while GNAQ^Q209R promotes adaptability, potentially via FAK-YAP signaling, nominating allele-stratified therapeutic opportunities.