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Conni Hanke, Andrew Dodson, Sarah Lake, Helen Kalirai, Sarah E Coupland; . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5340.
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© ARVO (1962-2015); The Authors (2016-present)
The liver is the main organ affected by metastatic uveal melanoma (MUM), but current treatments of metastases rarely prolong life and most patients die within a year of diagnosis. In this study, the genomic aberrations present in MUMs were identified and compared with those found in matched primary UMs (PUMs) to shed light into the molecular characteristics of these tumors.
DNA was extracted from 13 liver MUMs and six matched PUMs. The Affymetrix SNP Array 6.0 platform was used to detect copy number variations (CNVs), and data analysis was performed using the Partek Genomic Suite™ software. During analysis the samples were divided into different groups: (i) MUMs only, (ii) PUMs only, and (iii) matched PUM/MUM pairs.
Across the whole genome a broad spectrum of CNVs, mainly amplifications (87%), was observed, which confirmed the main chromosomal changes, i.e. deletions on chromosome (chr.) 3 and amplifications on chr. 8q. In total > 17000 genes with CNVs were detected for MUMs and > 20000 for PUMs. A group comparison of the MUMs with the PUMs found that the similarities between these groups varied, e.g., 94% of the amplifications on chr. 8q, but only 34% of the amplifications on chr. 9 were shared. Within the MUMs the most common CNVs were gene amplifications on chr. 8q, 20, 17, and 19 and gene deletions on chr. 3. Amplifications of the genes GNAQ and GNA11 (commonly mutated in PUM), were observed in 100% of PUMs but only 58% of MUMs; the BAP1 gene was deleted in 42% of MUMs and 40% of PUMs. CNVs of the SF3B1 and EIF1AX genes were not identified in MUMs, but the former was amplified in 60% and the latter deleted in 20% of PUMs. Other interesting genes like PTP4A3 or WISP1 were amplified in 100% of both, MUMs and PUMs. For the PUM/MUM pairs between > 4500 and > 20000 genes with CNVs were identified, and between 30-55% of commonly altered genes were found. However, the comparison also revealed that the more similar the CNVs on chr. 3 and chr. 8q in these pairs, the fewer CNVs were present on other chromosomes.
The genomic characterization of MUMs revealed a broad spectrum of CNVs with a high prevalence of amplifications on chr. 8q. Our data underline the importance of chr. 8q in UM metastatic disease. By validating the biological importance of specific gene amplifications in MUMs, novel therapeutic targets are likely to be identified.
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