Susan Kennedy1, Michael Rice1, Sinead Toomey2, Noel Horgan1, Bryan T Hennessey2, Annemarie Larkin3. 1. National Ophthalmic Laboratory, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, Ireland. 2. Department of Medical Oncology, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland. 3. National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. annemarie.larkin@dcu.ie.
Abstract
BACKGROUND/AIMS: Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance. METHODS: DNA was extracted from 36 intraocular melanoma patient samples and 4 metastatic melanoma samples among the patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel. RESULTS: Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM. CONCLUSION: Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.
BACKGROUND/AIMS: Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance. METHODS: DNA was extracted from 36 intraocular melanomapatient samples and 4 metastatic melanoma samples among the patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel. RESULTS: Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM. CONCLUSION: Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.
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