A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.
OBJECTIVE
To identify genes that modify metastatic risk in uveal melanoma, a type of cancer that is valuable for studying metastasis because of its remarkably consistent metastatic pattern and well-characterized gene expression signature associated with metastasis.


METHODS
We analyzed 53 primary uveal melanomas by gene expression profiling, array-based comparative genomic hybridization, array-based global DNA methylation profiling, and single nucleotide polymorphism-based detection of loss of heterozygosity to identify modifiers of metastatic risk. A candidate gene, leucine zipper tumor suppressor-1 (LZTS1), was examined for its effect on proliferation, migration, and motility in cultured uveal melanoma cells.


RESULTS
In metastasizing primary uveal melanomas, deletion of chromosome 8p12-22 and DNA hypermethylation of the corresponding region of the retained hemizygous 8p allele were associated with more rapid metastasis. Among the 11 genes located within the deleted region, LZTS1 was most strongly linked to rapid metastasis. LZTS1 was silenced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and nonmetastasizing uveal melanomas. Forced expression of LZTS1 in metastasizing uveal melanoma cells inhibited their motility and invasion, whereas depletion of LZTS1 increased their motility.


CONCLUSIONS
We have described a metastatic modifier locus on chromosome 8p and identified LZTS1 as a potential metastasis suppressor within this region. This study shows the utility of integrative genomic methods for identifying modifiers of metastatic risk in human cancers and may suggest new therapeutic targets in metastasizing tumor cells.
Onken
Michael D
MD
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Worley
Lori A
LA
Harbour
J William
JW
D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002898:Chromosomes, Human, Pair 8; D016000:Cluster Analysis; D015331:Cohort Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D023281:Genomics / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology*
D004268:DNA-Binding Proteins; C118711:LZTS1 protein, human; D025521:Tumor Suppressor Proteins