Abstract 855: Analysis of canonical uveal melanoma mutations reveals novel signaling effects

Abstract Uveal Melanoma (UM) is the most common primary ocular cancer in adults. Virtually all UM have activating mutations in the Gq signaling pathway. Metastatic risk in patients correlates with additional secondary mutations, where the lowest metastatic risk (class 1) is associated with EIF1AX and SF3B1, and the highest metastatic risk (class 2) is associated with BAP1 mutations. The interplay between the initiating Gq pathway mutations, and the secondary mutations found in all UM has not been well understood yet. Here, we utilize a multi-omics approach, to describe gene expression changes, the proteome, and phosphatome, following GNAQ mutation and BAP1 knockout in primary human uveal melanocytes. We generated human uveal melanocyte cell lines with inducible and specific mutations and analyzed via RNAseq, ATACseq, and mass spectrometry. Results reveal significant changes in pathways related to p53, chromatin regulation/modification, gene expression, and RNA processing with noted dysregulation of genes JUN, HDAC4, YAP, and SOX10, which cause senescence in melanocytes following GNAQ mutation, and are relieved through additional mutation in BAP1. Citation Format: Dawn Alexandra Owens, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Daniel A. Rodriguez, Anthony Cruz, J. Harbour. Analysis of canonical uveal melanoma mutations reveals novel signaling effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 855.