Zhilnikova M V, Troitskaya O S, Novak D D, Atamanov V V, Koval O A
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia.
Novosibirsk State University, Novosibirsk, 630090 Russia.
Mol Biol (Mosk). 2024 Mar-Apr;58(2):189-203.
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.
葡萄膜黑色素瘤（UM）是一种神经外胚层肿瘤，由眼部葡萄膜（包括虹膜、睫状体和脉络膜）中的黑素细胞恶性转化形成。UM占所有黑色素瘤病例的5%，极具侵袭性，半数UM患者在肿瘤发生后的头1 - 2年内会发生转移。UM致癌的分子机制尚不清楚，但已知与皮肤黑色素瘤不同。分别编码大G蛋白亚基Gq和G11的GNAQ和GNA11基因的激活突变在90%的UM患者中被发现。Gaq/PKC/MAPK信号通路是导致葡萄膜黑素细胞转化的主要信号级联反应，该级联反应的主要调节因子为药物开发提供了靶点。转移性UM（MUM）最常与BAP1、EIF1AX、GNA11、GNAQ和SF3B1的突变相关。一个包含15个基因的商业表达检测面板和一个包含7个基因的突变检测面板，再加上原发肿瘤大小的数据，在预测转移风险方面效率很高。转移风险决定了治疗方案的选择和患者的随访方案。然而，迄今为止尚未开发出针对MUM的全身治疗方法。正在进行临床试验的新药大多是旨在抑制突变基因蛋白质产物的靶向药物或旨在刺激针对特定抗原的免疫反应的免疫治疗药物。除了这些方法，本综述还考虑了UM发生表观遗传调控的潜在治疗靶点。
