title: A five-gene expression signature to predict progression in T1G3 bladder cancer.
abstract: The aim of this study was to analyze tumour gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BC) patients to develop a gene expression signature to predict tumour progression.
  
  
  
  Retrospective, multicenter study of 96 T1G3 BC patients without carcinoma in situ (CIS) who underwent a transurethral resection. Formalin-fixed paraffin-embedded tissue samples were collected. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BC patients using Illumina microarrays. Expression levels of 94 genes selected based on microarray data and based on literature were studied by quantitative polymerase chain reaction (qPCR) in an independent series of 75 progressive and non-progressive T1G3 BC patients. Univariate logistic regression was used to identify individual predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination of the model was measured by area under the receiver-operating characteristic curve. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin.
  
  
  
  A total of 1294 genes were found differentially expressed between progressive and non-progressive patients. Differential expression of 15 genes was validated by qPCR in an additional set of samples. A five-gene expression signature (ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1) discriminated progressive from non-progressive T1G3 BC patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Direct interactions between the five genes of the model were not found.
  
  
  
  Progressive and non-progressive T1G3 bladder tumours have shown different gene expression patterns. To identify T1G3 BC patients with a high risk of progression, a five-gene expression signature has been developed.
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Toine.vanderHeijden@radboudumc.nl.
authors.forename: Antoine G
authors.initials: AG
authors.lastname: van der Heijden
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. Electronic address: lmengual@clinic.ub.es.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mengual
authors.affiliation: CIBERehd, Plataforma de Bioinformática, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain. Electronic address: juanjo.lozano@Ciberehd.org.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. Electronic address: INGELMO@clinic.ub.es.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ingelmo-Torres
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. Electronic address: mjribal@clinic.ub.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ribal
authors.affiliation: Pathology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. Electronic address: PLFERNAN@clinic.ub.es.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Egbert.Oosterwijk@radboudumc.nl.
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Jack.Schalken@radboudumc.nl.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
authors.affiliation: Laboratory and Department of Urology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. Electronic address: ALCARAZ@clinic.ub.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcaraz
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Fred.Witjes@radboudumc.nl.
authors.forename: J Alfred
authors.initials: JA
authors.lastname: Witjes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017302:Annexins / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C121387:ANXA10 protein, human; D048868:Adaptor Proteins, Signal Transducing; D017302:Annexins; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C102885:DAB2 protein, human; D058851:GPI-Linked Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase
keywords: Biomarkers; Bladder cancer; Gene expression signature; Prognosis; Progressive disease