Whole-genome microarray detects deletions and loss of heterozygosity of chromosome 3 occurring exclusively in metastasizing uveal melanoma.

PURPOSE To detect deletions and loss of heterozygosity of chromosome 3 in a rare subset of fatal, disomy 3 uveal melanoma (UM), undetectable by fluorescence in situ hybridization (FISH). METHODS Multiplex ligation-dependent probe amplification (MLPA) with the P027 UM assay was performed on formalin-fixed, paraffin-embedded (FFPE) whole tumor sections from 19 disomy 3 metastasizing UMs. Whole-genome microarray analyses using a single-nucleotide polymorphism microarray (aSNP) were performed on frozen tissue samples from four fatal disomy 3 metastasizing UMs and three disomy 3 tumors with >5 years' metastasis-free survival. RESULTS Two metastasizing UMs that had been classified as disomy 3 by FISH analysis of a small tumor sample were found on MLPA analysis to show monosomy 3. No ubiquitous gene deletions of chromosome 3 were seen in the remaining 17 metastasizing disomy 3 UMs by MLPA. aSNP analysis revealed 95 deleted genes and 16 genes with loss of heterozygosity (LOH) on chromosome 3 in the disomy 3 metastasizing UMs that were not deleted or showing LOH in the nonmetastatic tumors. CONCLUSIONS MLPA can detect monosomy 3 cell populations in FFPE whole tumor sections previously missed by FISH performed on small tumor samples. Consistent deletion and LOH of genes on chromosome 3 occur in metastasizing disomy 3 UM and are detectable by aSNP analysis. Ninety-five genes were found to be deleted, and 16 genes showed LOH exclusively in disomy 3 metastasizing UM, suggesting a potential role for these genes in UM metastasis.