title: Muscle-invasive bladder cancer is characterized by overexpression of thymidine kinase 1.
abstract: OBJECTIVE
  Thymidine kinases have an important role in the synthesis of DNA and exhibit high activity in rapidly proliferating cells. Thymidine kinase 1 (TK1) activity has been shown to be increased in various cancer types and proposed as a prognostic parameter. Aim of the present study was to investigate TK1 in muscle-invasive urothelial carcinoma (UC).
  
  
  METHODS
  Corresponding UC and benign samples from paraffin embedded tissue of 111 patients treated with cystectomy for invasive UC from 1996 to 2006 were immunohistochemically (IHC) assessed for TK1. IHC expression patterns were evaluated in a semiquantitative fashion by 2 independent reviewers. Localization of staining was categorized into pure nuclear and additional cytoplasmic localization. Uni- and multivariate analyses were performed to assess differential expression in normal and UC tissue and to evaluate the diagnostic and predictive capability of TK1 by correlation to clinical data. To correlate TK1 expression with molecular subtypes of UC, analysis of TK1 RNA expression levels of the Cancer Genome Atlas UC cohort was performed.
  
  
  RESULTS
  TK1 was significantly overexpressed in invasive UC, compared to benign urothelium (P<0.0001), and cytoplasmic expression was more often found in cancer tissue than in benign tissue (P = 0.0001). No correlations of TK1 protein expression patterns to standard histopathological determinants were detected. In univariate analysis, TK1 nuclear and cytoplasmic expression was associated with improved cancer-specific survival (P = 0.0119). However, only metastasis status and histologic grade were identified as independent predictors of cancer-specific survival in multivariate analysis. TK1 expression was merely found in the basal layers of benign urothelium. RNA overexpression of TK1 could be correlated to the biologically more aggressive basal UC subtype.
  
  
  CONCLUSIONS
  TK1 expression is significantly different in invasive UC and benign urothelium, which underlines its potential as a diagnostic marker. Although TK1 is considered to be a marker of proliferation, and TK1 RNA overexpression is associated with an aggressive UC subtype, its capability as a predictive IHC biomarker for invasive UC remains limited.
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Hennenlotter
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Teepe
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kuehs
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aufderklamm
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Bier
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Mischinger
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Gakis
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwentner
authors.affiliation: Department of Urology, University Hospital, Eberhard-Karls-University, Tuebingen, Germany; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada. Electronic address: tilman.todenhoefer@med.uni-tuebingen.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D013937:Thymidine Kinase / Q000032:analysis / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D013937:Thymidine Kinase; C092717:thymidine kinase 1
keywords: Biomarker; Bladder cancer; Molecular subtypes; Proliferation; Thymidine kinase 1