Genomic profiling and identification of high-risk uveal melanoma by array CGH analysis of primary tumors and liver metastases.
OBJECTIVE
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.
Trolet
Julien
J
Department of Bioinformatics, Institut Curie, Paris, France.
Hupé
Philippe
P
Huon
Isabelle
I
Lebigot
Ingrid
I
Decraene
Charles
C
Delattre
Olivier
O
Sastre-Garau
Xavier
X
Saule
Simon
S
Thiéry
Jean-Paul
JP
Plancher
Corine
C
Asselain
Bernard
B
Desjardins
Laurence
L
Mariani
Pascale
P
Piperno-Neumann
Sophie
S
Barillot
Emmanuel
E
Couturier
Jérôme
J
D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D009006:Monosomy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm