TY - JOUR

T1 - Uveal Melanoma: Molecular and Genetic Mechanisms of Development and Therapeutic Approaches

AU - Zhilnikova, M. V.

AU - Troitskaya, O. S.

AU - Novak, D. D.

AU - Atamanov, V. V.

AU - Koval, O. A.

N1 - This work was supported by the Russian Science Foundation (project no. 23-14-00285; sections Molecular Mechanisms of Uveal Melanoma Development, Metastasis in Uveal Melanoma, Molecular Genetic Classification of Uveal Melanoma and Metastatic Risk Assessment, and Anticancer Therapy in Uveal Melanoma) and the budget funding project of the Institute of Chemical Biology and Fundamental Medicine (Siberian Branch, Russian Academy of Sciences) (project no. 121030200173-6; sections Uveal Melanoma and Melanocyte Origin and Functions).

PY - 2024/4

Y1 - 2024/4

N2 - Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1‒2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

AB - Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1‒2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

KW - BAP1

KW - GNAQ/11

KW - driver mutations

KW - epigenetic targets

KW - melanosomes

KW - tebentafusp

KW - uveal melanoma

KW - Humans

KW - Uveal Neoplasms/genetics

KW - Melanoma/genetics

KW - Mutation

KW - GTP-Binding Protein alpha Subunits/genetics

KW - Neoplasm Proteins/genetics

KW - Ubiquitin Thiolesterase/genetics

KW - GTP-Binding Protein alpha Subunits, Gq-G11/genetics

KW - Signal Transduction/drug effects

KW - Tumor Suppressor Proteins/genetics

KW - Gene Expression Regulation, Neoplastic/drug effects

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85190113807&origin=inward&txGid=3a3ddb2ae16f90fefa4ea66d0b73aa89

UR - https://www.webofscience.com/wos/woscc/full-record/WOS:001234925800001

UR - https://www.mendeley.com/catalogue/930c1fe0-cc95-3bdd-bdd7-55388badc019/

U2 - 10.1134/S0026893324020183

DO - 10.1134/S0026893324020183

M3 - Article

C2 - 39355878

VL - 58

SP - 165

EP - 177

JO - Molecular Biology

JF - Molecular Biology

SN - 0026-8933

IS - 2

ER -