GNAQ Q209L

This research experience imparts microscopy and image analysis skills and instills the ability to grapple with large datasets, statistical tests, and data interpretation in alignment with biology education principles. Post-laboratory surveys reveal students attain confidence in the above skills and in handling animals, along with a deeper appreciation for model organism research and its relevance to cancer cell biology.

Overexpression of oncogenic GnaqQ209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion.

However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

The established ddPCR assays are a valuable tool to detect the most frequent mutations in UM patients from ctDNA. These assays will allow serum and plasma genotyping, detection of MRD and monitoring of response to treatment to benefit UM patients and might support discrimination of uveal nevi from UM lesions.

Results may affect MUM care, treatment development, and trial stratification. More research is needed to confirm these findings.

Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

A decrease in the proliferation and metabolic activity was observed in Mel285GNAQ-KO and Mel285BAP1-KO cell lines in comparison to the wildtype cells. Furthermore, an increase of phosphorylated ATF2/7 was noted in Mel285GNAQ-KO and Mel285GNA11-KO cell lines by western blotting.A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically metastatic UM cells.

Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.

Our work also suggests a novel difference in sensitivity between the Gα Q209L, Gα Q209P, and Gα R183C mutants. We propose that disrupting the interaction between CA Gα and Gβγ can be a novel therapeutic target in UM.

We conclude that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and probably represent so-called "benign" metastasis. Awareness of these lesions is important when evaluating lymph nodes to avoid misdiagnosis as metastatic melanoma.

These results could potentially shift the concept of PRKAR1A-inactivated melanocytoma, changing from a rather unified model to a more complex one, including genetic subgroup variations with clinical and morphologic specificities. The genetic background of PRKAR1A-inactivated melanocytic tumors should be systematically explored to better understand the extent and clinical behavior of these complex lesions.