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Vishal Verma, Mohamed Abdel-Rahman, Benjamin Christopher, Colleen Cebulla, Frederick Davidorf; Monosomy 3 Status of Metastatic Uveal Melanomas is Associated with Rapidly Aggressive, Therapy-Resistant Tumors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5383.
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To investigate the molecular genetic status of uveal melanoma (UM) metastases and correlate it with disease progression and response to therapy.
Seven pathologically confirmed metastatic UM were studied. Four (57.1%) tumors were metastatic lesions in the liver, one from the peritoneum, one from the lung and one from bone lesions (14.3% each). Chromosomes 3, 8q, 6p, and 1p status were studied by microsatellite genotyping. Mutations in GNAQ and GNA11 genes were studied by restrictive fragment length polymorphism (RFLP). Correlation of molecular results with length of survival and response to therapy was determined by chart review. Mutations in GNAQ and GNA11 genes were studied by restrictive fragment length polymorphism (RFLP).
Monosomy of chromosome 3 with total loss of an allele was observed in all three tumors with rapid presentation of metastasis (average 21.3 months from treatment of primary UM) and rapid disease progression (average survival of 6 months from time of diagnosis of metastatic disease). In contrast, tumors with either disomy or partial chromosome 3 alterations had recurrence > 5 years after treatment of their primary UM (average of 144 months) and showed much slower metastatic disease progression with > 43 months survival (average 58 months). Chromosome 8q alterations were observed in all three tumors with rapidly progressive metastatic tumors and in 2/4 of the tumors with slowly progressive disease. Codon 209 mutations in GNAQ or GNA11 were observed in 5/7 metastatic tumors. GNAQ mutations were observed in 2/3 of the tumors with rapidly progressive disease and in 1/4 of the tumors with less aggressive disease, while GNA11 mutations were observed in 2/4 tumors with slowly progressive disease and in none of the tumors with rapidly progressive disease.
In metastatic UM, monosomy of chromosome 3, detected by genotyping, is associated with highly aggressive, rapidly progressive and therapy resistant disease. This finding should be considered when designing clinical trials testing effectiveness of various therapies.
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