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J. Harbour, L. A. Worley, A. Bowcock, D. H. Char, M. D. Onken; Chromosome 8p Status Predicts Disease-Free Survival in Aggressive Class 2 Uveal Melanomas. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1942.
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We have shown that primary uveal melanomas cluster into two distinct molecular groups that predict metastatic risk. Class 1 tumors are at low risk and class 2 tumors are at high risk of metastasis. The predictive accuracy of this molecular classification outperforms monosomy 3 and all clinicopathologic prognostic factors tested to date. However, the time interval from treatment of the ocular tumor to development of metastasis in patients with a class 2 tumor can range from a few months to many years. In this study, we analyzed clinical, pathologic and genetic factors to identify predictors of disease-free survival following ocular treatment.
Clinical and pathologic information was recorded on 53 patients treated by enucleation for uveal melanoma. Primary tumor tissue was analyzed by gene expression profiling, array comparative genomic hybridization (CGH), and single nucleotide polymorphism loss-of-heterozygosity analysis. Global genomic DNA methylation mapping was performed in six of the tumors using a methyl-DNA binding column and a CpG island microarray chip. Time-dependent statistical analysis was performed by the Cox proportional hazards and Kaplan-Meier methods.
The strongest predictor of metastasis was the class 2 gene expression signature. The only clinical, pathologic or chromosomal factor associated with shorter disease-free interval, independently of class 2 signature, was loss of chromosome 8p. Gene expression profiling of class 2 tumors revealed two sub-clusters of tumors: subgroup A tumors exhibited a longer disease-free interval and subgroup B tumors a shorter disease-free interval (P=0.04). The subgroup B gene expression signature was remarkable for a highly significant cluster of down-regulated genes on chromosome 8p (P<0.00001). Integrative global genomic analysis of chromosome 8p identified an interstitial deletion that coincided with a discrete zone of epigenetic silencing in rapidly metastasizing class 2/subgroup B tumors. A known tumor suppressor gene in this silenced chromosomal region was found to be inactivated in the rapidly metastasizing class 2 tumors.
Class 2 tumors can be subdivided into subgroup A (longer disease-free interval) and subgroup B (shorter disease-free interval) based on chromosome 8p status. Targeted deletion and hypermethylation of metastasis suppressor genes on 8p may lead to more rapid development of metastastic disease in subgroup B tumors. These finding provide further support for a new molecular classification of uveal melanoma.
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