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Originally published In Press as doi:10.1167/iovs.08-2033 on June 14, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4254-4262.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2033
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Gene Expression Profiling in Uveal Melanoma: Two Regions on 3p Related to Prognosis

Walter van Gils,1,2 Elisabeth M. Lodder,1 Hanneke W. Mensink,2,3 Emine Kiliç,1,2 Nicole C. Naus,2 Hennie T. Brüggenwirth,1 Wilfred van IJcken,4 Dion Paridaens,3 Gregorius P. Luyten,2,5 and Annelies de Klein1

1From the Departments of Clinical Genetics and 2Ophthalmology and the 4Center for Biomics, Erasmus MC, Rotterdam, The Netherlands; and the 3Rotterdam Eye Hospital, Rotterdam, The Netherlands.

PURPOSE. Although studies on uveal melanoma (UM) revealed prognostic significance of chromosomal aberrations, they resulted in classification errors in survival prediction. A robust prognostic classifier with strong predictive value and further insight in genes responsible for poor prognosis were obtained by performing a gene-expression profile in tumors of UM patients for which extensive clinical, histopathologic, cytogenetic, and follow-up data were available. Furthermore, the UM microarray expression data were compared with cytogenetic data.

METHODS. Gene-expression profiles of 46 UMs were obtained with microchip assays. Data were analyzed with cluster-analysis and predictive analysis of microarrays (PAM) software and validated with real-time PCR. The prognostic significance of UMs with specific molecular signatures was determined. Furthermore, LAP analysis resulted in the identification of differentially expressed chromosomal regions.

RESULTS. The primary UMs were classified in two distinct molecular classes with a strong prognostic value (P < 0.001; hazard ratio 7.7). Classifier gene sets for microarray class and disease-free survival were validated with real-time PCR, and the predictive value of the UM class marker set was validated with gene-expression profiles of tumors provided by other institutions, showing a sensitivity of 0.93 and specificity of 1.00 for class II tumors. A locally adaptive statistical procedure identified two regions on the short arm of chromosome 3 with decreased gene-expression in tumors with shorter disease-free survival.

CONCLUSIONS. Microarray classification outperforms known prognostic indicators for UM, such as clinical, histopathologic, and cytogenetic parameters. In addition, the identified regions with lower expressed genes on 3p could harbor genes that are responsible for the poor prognosis of patients with UM.






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