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Originally published In Press as doi:10.1167/iovs.08-2296 on January 17, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:2572-2580.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2296
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Genomic Profiling and Identification of High-Risk Uveal Melanoma by Array CGH Analysis of Primary Tumors and Liver Metastases

Julien Trolet,1,2,3 Philippe Hupé,1,2,3,4 Isabelle Huon,5 Ingrid Lebigot,6 Charles Decraene,7 Olivier Delattre,8 Xavier Sastre-Garau,9 Simon Saule,10 Jean-Paul Thiéry,7 Corine Plancher,11 Bernard Asselain,11 Laurence Desjardins,12 Pascale Mariani,13 Sophie Piperno-Neumann,14 Emmanuel Barillot,1,2,3 and Jérôme Couturier5,8

1From the Departments of Bioinformatics, 5Genetics, 7Translational Research, 9Pathology, 11Biostatistics, 12Ophthalmology, 13Surgery, and 14Medical Oncology, 2Institut National de la Santé et de la Recherche Médicale (INSERM) U900, 4CNRS (Centre National de la Recherche Scientifique) UMR144, 6Biological Resources Centre, 8INSERM U830, 10CNRS UMR146, Institut Curie, Paris, France; and 3Ecole des Mines de Paris, ParisTech, Fontainebleau, France.

PURPOSE. Incurable metastases develop in approximately 50% of patients with uveal melanoma (UM). The purpose of this study was to analyze genomic profiles in a large series of ocular tumors and liver metastases and design a genome-based classifier for metastatic risk assessment.

METHODS. A series of 86 UM tumors and 66 liver metastases were analyzed by using a BAC CGH (comparative genomic hybridization) microarray. A clustering was performed, and correlation with the metastatic status was sought among a subset of 71 patients with a minimum follow-up of 24 months. The status of chromosome 3 was further examined in the tumors, and metastases with disomy 3 were checked with an SNP microarray. A prognostic classifier was constructed using a log-linear model on minimal regions and leave-one-out cross-validation.

RESULTS. The clustering divides the groups of tumors with disomy 3 and monosomy 3 into two and three subgroups, respectively. Same subgroups are found in primary tumors and in metastases, but with different frequencies. Isolated monosomy 3 was present in 0% of metastatic ocular tumors and in 3% of metastases. The highest metastatic rate in ocular tumors was observed in a subgroup defined by the gain of 8q with a proximal breakpoint, and losses of 3, 8p, and 16q, also most represented in metastases. A prognostic classifier that included the status of these markers led to an 85.9% classification accuracy.

CONCLUSIONS. The analysis of the status of these specific chromosome regions by genome profiling on SNP microarrays should be a reliable tool for identifying high-risk patients in future adjuvant therapy protocols.






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