title: Identification of prefoldin amplification (1q23.3-q24.1) in bladder cancer using comparative genomic hybridization (CGH) arrays of urinary DNA.
abstract: BACKGROUND
  Array-CGH represents a comprehensive tool to discover genomic disease alterations that could potentially be applied to body fluids. In this report, we aimed at applying array-CGH to urinary samples to characterize bladder cancer.
  
  
  METHODS
  Urinary DNA from bladder cancer patients and controls were hybridized on 44K oligonucleotide arrays. Validation analyses of identified regions and candidates included fluorescent in situ hybridization (FISH) and immunohistochemistry in an independent set of bladder tumors spotted on custom-made tissue arrays (n = 181).
  
  
  RESULTS
  Quality control of array-CGH provided high reproducibility in dilution experiments and when comparing reference pools. The most frequent genomic alterations (minimal recurrent regions) among bladder cancer urinary specimens included gains at 1q and 5p, and losses at 10p and 11p. Supervised hierarchical clustering identified the gain at 1q23.3-q24.1 significantly correlated to stage (p = 0.011), and grade (p = 0.002). The amplification and overexpression of Prefoldin (PFND2), a selected candidate mapping to 1q23.3-q24.1, correlated to increasing stage and tumor grade by means of custom-designed and optimized FISH (p = 0.013 and p = 0.023, respectively), and immunohistochemistry (p ≤0.0005 and p = 0.011, respectively), in an independent set of bladder tumors included in tissue arrays. Moreover, PFND2 overexpression was significantly associated with poor disease-specific survival (p ≤0.0005). PFND2 was amplified and overexpressed in bladder tumors belonging to patients providing urinary specimens where 1q23.3q24.1 amplification was detected by array-CGH.
  
  
  CONCLUSIONS
  Genomic profiles of urinary DNA mirrowed bladder tumors. Molecular profiling of urinary DNA using array-CGH contributed to further characterize genomic alterations involved in bladder cancer progression. PFND2 was identified as a tumor stratification and clinical outcome prognostic biomarker for bladder cancer patients.
authors.affiliation: Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Melchor Fernandez Almagro 3, Madrid E-28029, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: López
authors.forename: Pilar
authors.initials: P
authors.lastname: González-Peramato
authors.forename: Javier
authors.initials: J
authors.lastname: Suela
authors.forename: Alvaro
authors.initials: A
authors.lastname: Serrano
authors.forename: Ferrán
authors.initials: F
authors.lastname: Algaba
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.forename: Oscar
authors.initials: O
authors.lastname: Heredero
authors.forename: Marta
authors.initials: M
authors.lastname: Sánchez-Carbayo
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor; D002878:Chromosomes, Human, Pair 1; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000652:urine*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics*; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000652:urine
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D018832:Molecular Chaperones; C112806:prefoldin; D004247:DNA
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