title: In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment.
abstract: An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.|Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Dam
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.
authors.forename: Pieter-Jan H H
authors.initials: PJ
authors.lastname: van Dam
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.|Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.|Phase I - Early Clinical Trials Unit, Oncology Department, University Hospital Antwerp UZA, Edegem, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.|Phase I - Early Clinical Trials Unit, Oncology Department, University Hospital Antwerp UZA, Edegem, Belgium.
authors.forename: Marco
authors.initials: M
authors.lastname: Giallombardo
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: van Berckelaer
authors.affiliation: Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Xuan Bich
authors.initials: XB
authors.lastname: Trinh
authors.affiliation: Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Sevilay
authors.initials: S
authors.lastname: Altintas
authors.affiliation: Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Manon
authors.initials: M
authors.lastname: Huizing
authors.affiliation: Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Kostas
authors.initials: K
authors.lastname: Papadimitriou
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.|Multidisciplinary Oncologic Centre Antwerp (MOCA), Edegem, Belgium.
authors.forename: Wiebren A A
authors.initials: WA
authors.lastname: Tjalma
authors.affiliation: Antwerp University Hospital, Centre of Oncologic Research (CORE) Antwerp University, Edegem, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: van Laere
mesh_terms: D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D019295:Computational Biology; D003198:Computer Simulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases
keywords: cancer; cervical carcinoma; in silico pathway analysis; treatment targets