PUBLICATION

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

Authors
Chen, E.Y., Dobrinski, K.P., Brown, K.H., Clagg, R., Edelman, E., Ignatius, M.S., Chen, J.Y., Brockmann, J., Nielsen, G.P., Ramaswamy, S., Keller, C., Lee, C., and Langenau, D.M.
ID
ZDB-PUB-130909-5
Date
2013
Source
PLoS Genetics   9(8): e1003727 (Journal)
Registered Authors
Dobrinski, Kim P., Langenau, David, Lee, Charles
Keywords
Zebrafish, Small interfering RNAs, Array CGH, Gene amplification, Gene expression, Gene regulation, Microarrays, Oncogenes
MeSH Terms
  • Animals
  • Genome, Human
  • Gene Expression Regulation, Neoplastic
  • Comparative Genomic Hybridization*
  • Zebrafish/genetics*
  • Oligonucleotide Array Sequence Analysis
  • Neoplasms/etiology
  • Neoplasms/genetics*
  • Oncogenes*
  • Rhabdomyosarcoma, Embryonal/genetics*
  • Rhabdomyosarcoma, Embryonal/pathology
  • Humans
  • In Situ Hybridization, Fluorescence
(all 13)
PubMed
24009521 Full text @ PLoS Genet.
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.

Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    embryonal rhabdomyosarcomaTAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    y1Tg
    1 - 1 of 1
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    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
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    Mapping
    No data available
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    Citation
    Chen, E.Y., Dobrinski, K.P., Brown, K.H., Clagg, R., Edelman, E., Ignatius, M.S., Chen, J.Y., Brockmann, J., Nielsen, G.P., Ramaswamy, S., Keller, C., Lee, C., and Langenau, D.M. (2013) Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genetics. 9(8):e1003727.