Integrative Genomic Analysis of Aneuploidy in Uveal Melanoma

Ehlers, Justis P.; Worley, Lori A.; Onken, Michael D.; Harbour, J. William

doi:10.1158/1078-0432.ccr-07-1825

Cited by 116 publications

(109 citation statements)

References 32 publications

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“…6 Here, we show that a second important event in metastatic progression is silencing of a region on 8p, which modifies the metastatic efficiency of class 2 tumor cells. This is consistent with our recent work showing that 8p loss is a late event in uveal melanoma progression (12).…”

Section: Discussionsupporting

confidence: 94%

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

Onken

Worley

Harbour

2008

Clinical Cancer Research

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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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Section: Discussionsupporting

confidence: 94%

“…Each chromosomal arm was scored as loss, normal, or gain. A more detailed analysis, along with references, has been published in a separate article (12).…”

Section: Methodsmentioning

confidence: 99%

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

Onken

Worley

Harbour

2008

Clinical Cancer Research

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“…20 PTEN inactivation is also associated with increased aneuploidy and decreased survival in UM. 20,21 Taken together, these findings implicate a role for PTEN in UM progression, indicating scope for further investigation in this area.…”

Section: Molecular Pathway Defects In Primary Ummentioning

confidence: 73%

“…Self-sufficiency in growth signals Gain of cell cycle stimulator-activation of pathways The PI3K-AKT prosurvival pathway is constitutively activated in UM. LOH of the PTEN locus occurs in 76% of UM [17][18][19][20][21] The RAF/MEK/ERK pathway is constitutively activated: activating mutations in GNAQ or GNA11 occur in 480% of UM and can activate the RAF/ MEK/ERK pathway 11,[22][23][24][25][26][27][28] …”

Section: The Hallmarks Of Cancermentioning

confidence: 99%

Molecular pathology of uveal melanoma

Coupland

Lake

Zeschnigk

et al. 2012

Eye

148

106

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Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligationdependent probe amplification, and singlenucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

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“…These showed characteristic CNAs (loss of 1p, 3, and 6q as well as gains of 6p and 8q; refs. [46][47][48].…”

Section: Copy Number Analysismentioning

confidence: 99%

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Griewank

Westekemper

Murali

et al. 2013

Clinical Cancer Research

188

187

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Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas.Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples.Results: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma.Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents.

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Integrative Genomic Analysis of Aneuploidy in Uveal Melanoma

Cited by 116 publications

References 32 publications

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

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

Molecular pathology of uveal melanoma

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

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