title: Cell cycle gene networks are associated with melanoma prognosis.
abstract: BACKGROUND
  Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an in vitro functional genomics approach to understand melanoma molecular pathways.
  
  
  RESULTS
  Affymetrix microarray data were generated from A375 melanoma cells treated in vitro with siRNAs against 45 transcription factors and signaling molecules. Analysis of this data using unsupervised hierarchical clustering and Bayesian gene networks identified proliferation-association RNA clusters, which were co-ordinately expressed across the A375 cells and also across melanomas from patients. The abundance in metastatic melanomas of these cellular proliferation clusters and their putative upstream regulators was significantly associated with patient prognosis. An 8-gene classifier derived from gene network hub genes correctly classified the prognosis of 23/26 metastatic melanoma patients in a cross-validation study. Unlike the RNA clusters associated with cellular proliferation described above, co-ordinately expressed RNA clusters associated with immune response were clearly identified across melanoma tumours from patients but not across the siRNA-treated A375 cells, in which immune responses are not active. Three uncharacterised genes, which the gene networks predicted to be upstream of apoptosis- or cellular proliferation-associated RNAs, were found to significantly alter apoptosis and cell number when over-expressed in vitro.
  
  
  CONCLUSIONS
  This analysis identified co-expression of RNAs that encode functionally-related proteins, in particular, proliferation-associated RNA clusters that are linked to melanoma patient prognosis. Our analysis suggests that A375 cells in vitro may be valid models in which to study the gene expression modules that underlie some melanoma biological processes (e.g., proliferation) but not others (e.g., immune response). The gene expression modules identified here, and the RNAs predicted by Bayesian network inference to be upstream of these modules, are potential prognostic biomarkers and drug targets.
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Hurley
authors.forename: Wendy
authors.initials: W
authors.lastname: Watkins
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Araki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tamada
authors.forename: Anita
authors.initials: A
authors.lastname: Muthukaruppan
authors.forename: Louis
authors.initials: L
authors.lastname: Ranjard
authors.forename: Eliane
authors.initials: E
authors.lastname: Derkac
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Crampin
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
mesh_terms: D001499:Bayes Theorem; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015201:Meta-Analysis as Topic; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors