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

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 (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. 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.

KEYWORDS:

• GNA11
• GNAQ
• HLA
• immunotherapy
• neoantigen
• uveal melanoma

Acknowledgments

We thank CERCA Program, Generalitat de Catalunya for institutional support. We also thank the Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP).

Disclosure statement

Dr Josep M Piulats has acted as a consultant or advisor for Roche, Novartis, Bristol Meyers Squibb, MSD Merck Serono, AstraZeneca, Clovis, VCN Biosciences, Janssen, Astellas, Bayer, Sanofi Genzyme, and Pfizer; received research funding from Pfizer, Merck Serono, MSD, Bristol Myers Squibb, Incyte, VCN Biosciences, Astellas, and Janssen; and received financial support for attending symposia from Roche, Janssen, and Ipsen.

Data availability statement

The data that support the findings of this study are openly available in TCGA repository.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2261278

Additional information

Funding

This work was supported by the Catalan Institute of Oncology, Aragon Government (Group B29_23R), grupo Español Multidisciplinar de Melanoma (GEM), through the call “I Beca GEM al mejor proyecto GEM” and also has been funded by Instituto de Salud Carlos III through the grant [INT21/00056]. Sandra Garcia receives fund from PID2021-128343OB-I00 project from MCIN/AEI/10.13039/501100011033/FEDER, UE). We thank CERCA Programme/Generalitat de Catalunya for institutional support.