title: Prognostication of prostate cancer based on TOP2A protein and gene assessment: TOP2A in prostate cancer.
abstract: BACKGROUND
  TOP2A encodes for topoisomerase IIα, a nuclear enzyme that controls DNA topological structure and cell cycle progression. This enzyme is a marker of cell proliferation in normal and neoplastic tissues; however, little information is available about its expression in prostate cancer (PCa).
  
  
  METHODS
  Immunohistochemistry (IHC) was automated using mouse monoclonal antibody against TOP2A (clone SWT3D1; DAKO, Carpenteria, CA, USA) at dilution 1:800 and Flex Plus detection system in autostainer 48Ultra (DAKO). FISH was performed using TOP2A (17q21)/ CEP17 probe kit (Kreateck Biotechnology, San Diego, CA, USA). Biochemical and pathological data from 193 patients with PCa were retrieved for the analysis, whose significance was considered when p < 0.05. Also, fractal analysis was performed in a subset of 20 randomly selected cases.
  
  
  RESULTS
  TOP2A protein expression correlated with higher Gleason scores and higher levels of preoperative PSA (p = 0.018 and p = 0.011). Patients with higher levels of TOP2A presented shorter biochemical recurrence-free survival (BRFS) (p = 0.001). In multivariate analysis, we found that TOP2A remained an independent prognostic factor of BRFS, with a relative risk of 1.98 (p = 0.001; 95% CI, 1.338-2.93); thus, cases that expressed high levels of this enzyme had a shorter BRFS compared with TOP2A-negative or TOP2A-low cases. No alterations in TOP2A gene status nor correlation between FISH and IHC results were observed. Concerning fractal analysis, patients who expressed higher levels of TOP2A have angiolymphatic invasion and presented higher Gleason scores (p = 0.033 and p = 0.025, respectively). Also, patients with higher expression of TOP2A presented shorter BRFS (p = 0.001).
  
  
  CONCLUSIONS
  This is the first study to perform TOP2A protein and gene digital assessment and fractal analysis in association with BRFS in a large series of PCa. Also, we show that TOP2A gene copy number alterations are not observed in this type of tumor. So, higher protein expression of TOP2A is not related to gene amplification in PCa. Furthermore, TOP2A protein assessment has prognostic importance and, due to its relation with poor outcome, TOP2A IHC evaluation in the biopsy can represent an important tool for selecting the most suitable surgical and clinical approach for patients with PCa.
authors: Department of Pathology, A. C. Camargo Cancer Hospital, Sao Paulo, Brazil.
authors: Marina França
authors: MF
authors: de Resende
authors: Samantha
authors: S
authors: Vieira
authors: Ludmilla Thomé Domingos
authors: LT
authors: Chinen
authors: Francesco
authors: F
authors: Chiappelli
authors: Francisco Paulo
authors: FP
authors: da Fonseca
authors: Gustavo Cardoso
authors: GC
authors: Guimarães
authors: Fernando Augusto
authors: FA
authors: Soares
authors: Ivan
authors: I
authors: Neves
authors: Simone
authors: S
authors: Pagotty
authors: Peter A
authors: PA
authors: Pellionisz
authors: Andre
authors: A
authors: Barkhordarian
authors: Xenia
authors: X
authors: Brant
authors: Rafael Malagoli
authors: RM
authors: Rocha
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D017709:Fractals; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse
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