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

Abstract

Purpose: 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. Experimental Design: 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 LZTS1increased 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.Metastasis is the leading cause of death in cancer patients.However, the genetic mechanisms governing metastasis remain poorly understood. Indeed, dozens of oncogenes and tumor suppressor genes involved in early tumorigenesis have been characterized, but only about 10 metastasis suppressor genes have been identified (1). The search for new metastasis modifier loci has been hampered by the enormous complexity of the metastatic process, involving local invasion, entry into the circulation or lymphatic system, survival from hemodynamic shear stresses in the circulation, evasion of the immune system, and then extravasation, migration, proliferation, and recruitment of a blood supply at the metastatic site (2). Consequently, genetic modifiers of metastasis have been studied mostly in model organisms (1, 3). Our goal is to identify such modifiers in human cancers through whole-genome analytical techniques.Uveal melanoma is valuable for studying modifiers of metastatic efficiency in a human cancer. Metastasis occurs in about half of these cancers and is uniformly fatal within a few months (4). Because of the anatomic constraints of the eye, uveal melanoma does not spread by local invasion or lymphatic dissemination but exclusively by the hematogenous route. Further, gene expression profiling of primary uveal melanomas has revealed two molecula...

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LZTS1 (leucine zipper, putative tumor suppressor 1)

“…Moreover overexpression of LZTS1 in metastasizing uveal melanoma-derived cells inhibited their motility and invasion (Onken et al, 2008).…”