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Article: Gene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma
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TitleGene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma
 
AuthorsIvanovska, I2 3
Zhang, C2 3
Liu, AM1 5
Wong, KF5
Lee, NP1
Lewis, P3
Philippar, U2
Bansal, D2
Buser, C4
Scott, M2
Mao, M6 3
Poon, RTP1
Fan, ST1
Cleary, MA3 4
Luk, JM1 5
Dai, H2 3
 
Issue Date2011
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPlos One, 2011, v. 6 n. 9 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0024582
 
AbstractBiomarkers derived from gene expression profiling data may have a high false-positive rate and must be rigorously validated using independent clinical data sets, which are not always available. Although animal model systems could provide alternative data sets to formulate hypotheses and limit the number of signatures to be tested in clinical samples, the predictive power of such an approach is not yet proven. The present study aims to analyze the molecular signatures of liver cancer in a c-MET-transgenic mouse model and investigate its prognostic relevance to human hepatocellular carcinoma (HCC). Tissue samples were obtained from tumor (TU), adjacent non-tumor (AN) and distant normal (DN) liver in Tet-operator regulated (TRE) human c-MET transgenic mice (n = 21) as well as from a Chinese cohort of 272 HBV- and 9 HCV-associated HCC patients. Whole genome microarray expression profiling was conducted in Affymetrix gene expression chips, and prognostic significances of gene expression signatures were evaluated across the two species. Our data revealed parallels between mouse and human liver tumors, including down-regulation of metabolic pathways and up-regulation of cell cycle processes. The mouse tumors were most similar to a subset of patient samples characterized by activation of the Wnt pathway, but distinctive in the p53 pathway signals. Of potential clinical utility, we identified a set of genes that were down regulated in both mouse tumors and human HCC having significant predictive power on overall and disease-free survival, which were highly enriched for metabolic functions. In conclusions, this study provides evidence that a disease model can serve as a possible platform for generating hypotheses to be tested in human tissues and highlights an efficient method for generating biomarker signatures before extensive clinical trials have been initiated. © 2011 Ivanovska et al.
 
ISSN1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0024582
 
PubMed Central IDPMC3174972
 
ISI Accession Number IDWOS:000295173800028
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorIvanovska, I
 
dc.contributor.authorZhang, C
 
dc.contributor.authorLiu, AM
 
dc.contributor.authorWong, KF
 
dc.contributor.authorLee, NP
 
dc.contributor.authorLewis, P
 
dc.contributor.authorPhilippar, U
 
dc.contributor.authorBansal, D
 
dc.contributor.authorBuser, C
 
dc.contributor.authorScott, M
 
dc.contributor.authorMao, M
 
dc.contributor.authorPoon, RTP
 
dc.contributor.authorFan, ST
 
dc.contributor.authorCleary, MA
 
dc.contributor.authorLuk, JM
 
dc.contributor.authorDai, H
 
dc.date.accessioned2011-12-02T05:19:30Z
 
dc.date.available2011-12-02T05:19:30Z
 
dc.date.issued2011
 
dc.description.abstractBiomarkers derived from gene expression profiling data may have a high false-positive rate and must be rigorously validated using independent clinical data sets, which are not always available. Although animal model systems could provide alternative data sets to formulate hypotheses and limit the number of signatures to be tested in clinical samples, the predictive power of such an approach is not yet proven. The present study aims to analyze the molecular signatures of liver cancer in a c-MET-transgenic mouse model and investigate its prognostic relevance to human hepatocellular carcinoma (HCC). Tissue samples were obtained from tumor (TU), adjacent non-tumor (AN) and distant normal (DN) liver in Tet-operator regulated (TRE) human c-MET transgenic mice (n = 21) as well as from a Chinese cohort of 272 HBV- and 9 HCV-associated HCC patients. Whole genome microarray expression profiling was conducted in Affymetrix gene expression chips, and prognostic significances of gene expression signatures were evaluated across the two species. Our data revealed parallels between mouse and human liver tumors, including down-regulation of metabolic pathways and up-regulation of cell cycle processes. The mouse tumors were most similar to a subset of patient samples characterized by activation of the Wnt pathway, but distinctive in the p53 pathway signals. Of potential clinical utility, we identified a set of genes that were down regulated in both mouse tumors and human HCC having significant predictive power on overall and disease-free survival, which were highly enriched for metabolic functions. In conclusions, this study provides evidence that a disease model can serve as a possible platform for generating hypotheses to be tested in human tissues and highlights an efficient method for generating biomarker signatures before extensive clinical trials have been initiated. © 2011 Ivanovska et al.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationPlos One, 2011, v. 6 n. 9 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0024582
 
dc.identifier.citeulike11367281
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0024582
 
dc.identifier.hkuros197816
 
dc.identifier.isiWOS:000295173800028
 
dc.identifier.issn1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
dc.identifier.issue9
 
dc.identifier.pmcidPMC3174972
 
dc.identifier.pmid21949730
 
dc.identifier.scopuseid_2-s2.0-80052841535
 
dc.identifier.urihttp://hdl.handle.net/10722/143475
 
dc.identifier.volume6
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS ONE
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshCarcinoma, Hepatocellular - diagnosis - genetics - metabolism - pathology
 
dc.subject.meshLiver - cytology - metabolism - pathology
 
dc.subject.meshLiver Neoplasms - diagnosis - genetics - metabolism - pathology
 
dc.subject.meshProto-Oncogene Proteins c-met - genetics
 
dc.subject.meshTranscriptome
 
dc.titleGene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma
 
dc.typeArticle
 
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<contributor.author>Lee, NP</contributor.author>
<contributor.author>Lewis, P</contributor.author>
<contributor.author>Philippar, U</contributor.author>
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<subject.mesh>Carcinoma, Hepatocellular - diagnosis - genetics - metabolism - pathology</subject.mesh>
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Author Affiliations
  1. The University of Hong Kong
  2. Merck Research Laboratories
  3. Rosetta Inpharmatics LLC
  4. Merck &amp; Co.
  5. National University of Singapore
  6. Pfizer