Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma

Abstract

Purpose: Loss of chromosome 3 is strongly associated with metastasis in uveal melanoma and has been proposed as the basis for clinical prognostic testing. It is not known whether techniques that identify loss of heterozygosity for chromosome 3 predict metastasis more accurately than those that detect only numerical loss of chromosome 3 (monosomy 3). Experimental Design: Fifty-three uveal melanomas were analyzed by 28 single nucleotide polymorphisms (SNP) across chromosome 3. SNP was compared with fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) for metastasis prediction by sensitivity, specificity, and Kaplan-Meier survival analysis, using our validated gene expression-based classifier as a reference standard. Results: By Kaplan-Meier analysis, only the gene expression-based classifier (P = 0.001) and SNP-based detection of loss of heterozygosity for chromosome 3 (P = 0.04) were significantly associated with metastasis. Sensitivity and specificity were 95.2% and 80.8%, respectively, for SNP, 77.8% and 64.7%, respectively, for FISH, and 85.0% and 72.0%, respectively, for aCGH. Isodisomy 3 was identified by SNP but undetected by aCGH and FISH in three tumors. Conclusions: Prognostic tests based on SNP platforms, which detect both chromosomal homologues and their subregions, may be superior to techniques that only detect changes in chromosome number. These observations could have important implications for efforts to detect genetic alterations in cancer genomes with CGH-based approaches.Uveal melanoma is the most common primary cancer of the eye and has a strong predilection for hematogenous metastasis, particularly to the liver (1). Up to half of uveal melanoma patients develop metastasis with a median time of 2.4 years from ocular diagnosis, usually leading to death within a few months (2). This has lead some investigators to propose that high-risk patients should be treated with prophylactic systemic therapy (3). However, an accurate prognostic classifier for identifying high-risk patients who may benefit from prophylactic therapy has not been validated.Many clinical and pathologic features have been associated with metastatic disease, but none of these has been shown to have adequate sensitivity and specificity for making personalized clinical decisions. Monosomy 3, detected by cytogenetic analysis, spectral karyotyping, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and other techniques, may be more accurate than clinical and pathologic features and has been adopted as a molecular prognostic marker in many centers (4 -12). More recently, two distinct molecular subgroups were identified by gene expression profiling that correlate strongly with metastatic risk (13,14). Tumors with the class 1 expression signature had a low risk, and those with the class 2 signature had a high risk of metastasis. Although there was a strong association between the class 2 signature and monosomy 3, the gene expression-based classifier w...

Let-7b and microRNA-199a inhibit the proliferation of B16F10 melanoma cells

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Integrative Genomic Analysis of Aneuploidy in Uveal Melanoma

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A Metastasis Modifier Locus on Human Chromosome 8p in Uveal Melanoma Identified by Integrative Genomic Analysis

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