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Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma.

Chen EY, Dobrinski KP, Brown KH, Clagg R, Edelman E, Ignatius MS, Chen JY, Brockmann J, Nielsen GP, Ramaswamy S, Keller C, Lee C, Langenau DM - PLoS Genet. (2013)

Bottom Line: Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS--identifying critical genes associated with tumor maintenance.PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth.By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.

ABSTRACT
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS--identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.

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Elevated VEGFA expression correlates with poor clinical outcome in rhabdomyosarcoma.Kaplan-Meier analysis was completed using microarray gene expression data for which patient outcome is available. Comparison was made in all RMS patients, ERMS patients only, and translocation-positive ARMS patients only. (A) HOXC6. (B) VEGFA.
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pgen-1003727-g007: Elevated VEGFA expression correlates with poor clinical outcome in rhabdomyosarcoma.Kaplan-Meier analysis was completed using microarray gene expression data for which patient outcome is available. Comparison was made in all RMS patients, ERMS patients only, and translocation-positive ARMS patients only. (A) HOXC6. (B) VEGFA.

Mentions: To assess whether dysregulated expression of CCND2, HOXC6, PLXNA1 and VEGFA correlates with clinical outcome, Kaplan Meier analyses were completed using microarray gene expression data from primary ERMS and ARMS [23]. Samples were stratified based on high and low median expression for each gene and each assessed as an independent predictor of survival. Based on this analysis, differential expression of CCND2 and PLXNA1 did not correlate with overall survival outcome in either ERMS or ARMS (Fig. S8). HOXC6 was differentially upregulated in ERMS compared to ARMS (Fig. S7); thus, high expression of HOXC6 correlated with better overall survival (Fig. 7 A), a finding consistent with previous studies demonstrating better clinical outcome for ERMS patients compared to those with ARMS [27]. Finally, samples with high mRNA expression of VEGFA correlated with low overall clinical survival in the ERMS cohort but did not predict survival outcome in ARMS (Fig. 7 B). In addition, VEGFA expression did not correlate with clinical stage, indicating that it is likely an independent prognostic indicator (Fig. S9). These data implicate important roles of VEGFA in promoting ERMS tumor progression and identify VEGFA as a biomarker with likely use in stratifying ERMS patients into high and low-risk groups.


Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma.

Chen EY, Dobrinski KP, Brown KH, Clagg R, Edelman E, Ignatius MS, Chen JY, Brockmann J, Nielsen GP, Ramaswamy S, Keller C, Lee C, Langenau DM - PLoS Genet. (2013)

Elevated VEGFA expression correlates with poor clinical outcome in rhabdomyosarcoma.Kaplan-Meier analysis was completed using microarray gene expression data for which patient outcome is available. Comparison was made in all RMS patients, ERMS patients only, and translocation-positive ARMS patients only. (A) HOXC6. (B) VEGFA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757044&req=5

pgen-1003727-g007: Elevated VEGFA expression correlates with poor clinical outcome in rhabdomyosarcoma.Kaplan-Meier analysis was completed using microarray gene expression data for which patient outcome is available. Comparison was made in all RMS patients, ERMS patients only, and translocation-positive ARMS patients only. (A) HOXC6. (B) VEGFA.
Mentions: To assess whether dysregulated expression of CCND2, HOXC6, PLXNA1 and VEGFA correlates with clinical outcome, Kaplan Meier analyses were completed using microarray gene expression data from primary ERMS and ARMS [23]. Samples were stratified based on high and low median expression for each gene and each assessed as an independent predictor of survival. Based on this analysis, differential expression of CCND2 and PLXNA1 did not correlate with overall survival outcome in either ERMS or ARMS (Fig. S8). HOXC6 was differentially upregulated in ERMS compared to ARMS (Fig. S7); thus, high expression of HOXC6 correlated with better overall survival (Fig. 7 A), a finding consistent with previous studies demonstrating better clinical outcome for ERMS patients compared to those with ARMS [27]. Finally, samples with high mRNA expression of VEGFA correlated with low overall clinical survival in the ERMS cohort but did not predict survival outcome in ARMS (Fig. 7 B). In addition, VEGFA expression did not correlate with clinical stage, indicating that it is likely an independent prognostic indicator (Fig. S9). These data implicate important roles of VEGFA in promoting ERMS tumor progression and identify VEGFA as a biomarker with likely use in stratifying ERMS patients into high and low-risk groups.

Bottom Line: Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS--identifying critical genes associated with tumor maintenance.PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth.By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.

ABSTRACT
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS--identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.

Show MeSH
Related in: MedlinePlus