Article: Gene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma

File Download Links for fulltext
(May Require Subscription)
Supplementary
  • Basic View
  • Metadata View
  • XML View
TitleGene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma
AuthorsIvanovska, I1 3
Zhang, C1 3
Liu, AM2 4
Wong, KF4
Lee, NP2
Lewis, P3
Philippar, U1
Bansal, D1
Buser, C3
Scott, M1
Mao, M3 5
Poon, RTP2
Fan, ST2
Cleary, MA3
Luk, JM2 4
Dai, H1 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
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
DOIhttp://dx.doi.org/10.1371/journal.pone.0024582
ISI Accession Number IDWOS:000295173800028
PubMed Central IDPMC3174972
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
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
Author Affiliations
  1. Merck Research Laboratories
  2. The University of Hong Kong
  3. Merck & Co.
  4. National University of Singapore
  5. Pfizer