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 GNAQQ209L and GNAQQ209R in an otherwise matched genetic context. Tumors arising from either allele shared similar histology and cell-state composition. However, GNAQQ209L tumors progressed faster and were associated with reduced survival. In contrast, GNAQQ209R tumor-derived cell lines exhibited greater ex vivo fitness (proliferation, clonogenicity, and migration), whereas GNAQQ209L-derived lines were relatively fragile in 2D culture. At the molecular level, GNAQQ209R 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 GNAQQ209L favors rapid in vivo expansion, while GNAQQ209R promotes adaptability, potentially via FAK-YAP signaling, nominating allele-stratified therapeutic opportunities.

Abstract from PubMed