title: DHH is an independent prognosticator of oncologic outcome of clear cell renal cell carcinoma.
abstract: OBJECTIVE
  Aberrant HH signaling has proved important in the pathogenesis of several solid cancers. Limited in vitro analyses suggested an oncogenic role for HH in renal cell carcinoma. In this explorative study we sought to validate aberrant HH expression in patients with renal cell carcinoma.
  
  
  METHODS
  A tissue microarray was constructed from 140 radical nephrectomy specimens of patients with clear cell renal cell carcinoma. We performed immunohistochemistry for Ki67 and HH pathway biomarkers, including PTCH1, Smo, SHH, IHH, DHH, Gli1, Gli2 and Gli3. Staining intensity was measured by automated image processing and related to tumor stage and grade. The impact of biomarker expression on cancer specific survival was determined by univariate and multivariate Cox regression analysis.
  
  
  RESULTS
  Gli3, PTCH1, DHH and SHH demonstrated markedly higher expression in high than in low grade tumors. Tumor stage was not associated with marker expression. On univariate analysis DHH expression, and tumor grade and stage were associated with cancer specific survival. Multivariate analysis revealed that DHH, grade and stage were independent predictors of cancer specific survival.
  
  
  CONCLUSIONS
  To our knowledge we report for the first time that a biomarker of the HH pathway is associated with adverse pathological features and poor disease outcomes in patients with clear cell renal cell carcinoma. DHH may serve as an independent predictor of cancer specific survival in clear cell renal cell carcinoma cases. This supports further evaluation of HH signaling to validate the pathway as a target for novel therapy.
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Estelle
authors.initials: E
authors.lastname: Li
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kilian M
authors.initials: KM
authors.lastname: Gust
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alan I
authors.initials: AI
authors.lastname: So
authors.affiliation: Institute of Pathology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hainz
authors.affiliation: Institute of Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Schmidtmann
authors.affiliation: Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Frederik C
authors.initials: FC
authors.lastname: Roos
authors.affiliation: Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Thüroff
authors.affiliation: Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Walburgis
authors.initials: W
authors.lastname: Brenner
authors.affiliation: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: pblack@mail.ubc.ca.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000096:biosynthesis*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D053823:Hedgehog Proteins
keywords: biological markers; carcinoma; hedgehog proteins; kidney; mortality; renal cell