BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Unlike other clinical subtypes of melanoma, uveal melanomas rarely if ever involve mutations in BRAF, NRAS, or KIT. The dominant genetic alterations observed in uveal melanomas are somatic activating mutations in one of two heterotrimeric G protein a-subunits: GNAQ and GNA11. These mutations are almost never concomitant and are exclusively found in 80% of uveal melanomas, with GNAQ and GNA11 each affected in 40% of uveal melanomas. GNAQ and GNA11 mutations are also commonly found in proliferations of dermal melanocytes called blue nevi. In contrast, GNAQ and GNA11 mutations were only found in 1 of 273 (0.4%) of extraocular melanomas [104, 105].
G protein a-subunits are GTPases that serve as molecular switches for the G protein, which is active in its GTP-bound state and inactive in its GDP-bound state. In uveal melanoma, GNAQ and GNA11 mutations are restricted to codon R183 in exon 4 and codon Q209 in exon 5 , and their effect is to trap GNAQ and GNA11 in their active, GTP-bound states [106, 107]. As a result, GNAQ and GNA11 mutations contribute to uveal melanomagenesis by activating signaling of numerous pathways regulated by GPCRs including the MAPK pathway .
Interestingly, when taken together, the incidence of GNAQ and GNA11 mutations is not higher in uveal melanoma metastases than in primary uveal melanomas. However, in one study of 187 patients GNAQ mutations were proportionally more common in primary uveal melanomas while GNA11 mutations were found in a greater fraction of metastases, suggesting that stratifying by affected G protein a-subunit may be clinically useful .
Loss of the tumor suppressor BRCA1-associated protein (BAP1) on chromosome 3 is associated with metastatic uveal melanoma. BAP1 encodes a deubiquitinase that is a component of Polycomb-repressive complexes. Loss of BAP1 in uveal melanoma is thought to most often result from loss of one chromosome 3 allele combined with somatic mutation in the other BAP1 allele. Complete or partial monosomy of chromosome 3 occurs in about 25% of uveal melanomas .
While uveal melanoma may be diagnosed at relatively early stages due to visual symptoms, the disease has a striking propensity to metastasize to the liver. BAP1 mutation predicts poor clinical outcome and is particularly associated with risk of metastatic disease: in one study BAP1 was mutated in 84% of uveal melanomas from patients at high risk for metastasis but only 4% of tumors from patients at low risk for metastasis .
Germline BAP1 mutation or loss predisposes individuals to malignancy, with familial uveal melanoma accounting for 2–5% of all uveal melanoma cases. However, penetrance of disease is relatively low in these families, perhaps because inactivation of BAP1 occurs as a late event in melanoma progression .
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