title: Large differences in global transcriptional regulatory programs of normal and tumor colon cells.
abstract: BACKGROUND
  Dysregulation of transcriptional programs leads to cell malfunctioning and can have an impact in cancer development. Our study aims to characterize global differences between transcriptional regulatory programs of normal and tumor cells of the colon.
  
  
  METHODS
  Affymetrix Human Genome U219 expression arrays were used to assess gene expression in 100 samples of colon tumor and their paired adjacent normal mucosa. Transcriptional networks were reconstructed using ARACNe algorithm using 1,000 bootstrap replicates consolidated into a consensus network. Networks were compared regarding topology parameters and identified well-connected clusters. Functional enrichment was performed with SIGORA method. ENCODE ChIP-Seq data curated in the hmChIP database was used for in silico validation of the most prominent transcription factors.
  
  
  RESULTS
  The normal network contained 1,177 transcription factors, 5,466 target genes and 61,226 transcriptional interactions. A large loss of transcriptional interactions in the tumor network was observed (11,585; 81% reduction), which also contained fewer transcription factors (621; 47% reduction) and target genes (2,190; 60% reduction) than the normal network. Gene silencing was not a main determinant of this loss of regulatory activity, since the average gene expression was essentially conserved. Also, 91 transcription factors increased their connectivity in the tumor network. These genes revealed a tumor-specific emergent transcriptional regulatory program with significant functional enrichment related to colorectal cancer pathway. In addition, the analysis of clusters again identified subnetworks in the tumors enriched for cancer related pathways (immune response, Wnt signaling, DNA replication, cell adherence, apoptosis, DNA repair, among others). Also multiple metabolism pathways show differential clustering between the tumor and normal network.
  
  
  CONCLUSIONS
  These findings will allow a better understanding of the transcriptional regulatory programs altered in colon cancer and could be an invaluable methodology to identify potential hubs with a relevant role in the field of cancer diagnosis, prognosis and therapy.
authors.forename: David
authors.initials: D
authors.lastname: Cordero
authors.forename: Xavier
authors.initials: X
authors.lastname: Solé
authors.forename: Marta
authors.initials: M
authors.lastname: Crous-Bou
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanz-Pamplona
authors.forename: Laia
authors.initials: L
authors.lastname: Paré-Brunet
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guinó
authors.forename: David
authors.initials: D
authors.lastname: Olivares
authors.forename: Antonio
authors.initials: A
authors.lastname: Berenguer
authors.forename: Cristina
authors.initials: C
authors.lastname: Santos
authors.forename: Ramón
authors.initials: R
authors.lastname: Salazar
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Biondo
authors.affiliation: Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Av Gran Via 199-203, E-08907 L'Hospitalet de Llobregat, Barcelona, Spain. v.moreno@iconcologia.net.
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
mesh_terms: D016000:Cluster Analysis; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D009154:Mutation; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D059467:Transcriptome