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bioRxiv · 10.1101/2022.09.28.509834

Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients

Garcia-Mulero, S.·Fornelino, R.·Punta, M.·Lise, S.·Varela, M.·Moreno, R.·Costa-Garcia, M.·Gros, A.·Alemany, R.·Piulats, J. M.·Sanz-Pamplona, R.
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Abstract

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (aminoacid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and do not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data for primary uveal tumors was collected from TCGA-UM dataset (n=80). The immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations was assessed using a variety of tools and HLA types information. The immune microenvironment was characterized using gene expression data. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000G database whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Samples carrying Q209L had a higher immune-reactive phenotype: (i) expression of antigen presenting genes HLA-A (p=0.009) and B2M (p=0.043); (ii) immunophenoscore (p=0.008); (iii) infiltration of immune system cells NK (p=0.002) and CD8+ T lymphocytes (p=0.02). 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.

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Garcia-Mulero, S., Fornelino, R., Punta, M., Lise, S., Varela, M., Moreno, R., Costa-Garcia, M., Gros, A., Alemany, R., Piulats, J. M., Sanz-Pamplona, R.. 2022-09-28. Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients. https://doi.org/10.1101/2022.09.28.509834

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