title: TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy.
abstract: BACKGROUND
  Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP).
  
  
  METHODS
  The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody. Staining intensity was recorded by two independent observers using a four-tired semi-quantitative grading system (0, 1+, 2+, 3+) converted into H-scores. Interobserver agreement was calculated by linear weighted kappa statistics. The association between staining intensity and BR was analysed using the Kaplan-Meier estimator and uni- and multiple Cox proportional hazard regression models.
  
  
  RESULTS
  Significantly higher staining intensity was found in PCa glands compared to benign glands (p < 0.001). The concordance rate in TRPM4 staining intensities for benign, PIN and PCa tissue ranged from 86.0 to 91.5 %, corresponding to linear weighted kappa values of 0.566-0.789. After adjusting for patient and tumour characteristics, patients with a higher staining intensity in PCa glands compared to matched benign glands and an H-score equal to or above the median had an increased risk of BR (HR 1.79-2.62; p = 0.01-0.03 for the two observers) when compared to patients with a lower staining intensity.
  
  
  CONCLUSIONS
  TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue, with highest staining intensities found in PCa. Overexpression of TRPM4 in PCa (combination of high staining intensity and a high H-score) is associated with increased risk of BR after RP.
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kasper Drimer
authors.initials: KD
authors.lastname: Berg
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich (USZ), Zurich, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Soldini
authors.affiliation: Institute of Pathology, University Hospital Bonn (UKB), Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Pathology, University Hospital Bonn (UKB), Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Department of Urology, Charité University Hospital, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stephan
authors.affiliation: Berlin Institute for Urologic Research, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.affiliation: Institute of Pathology, University Hospital Bonn (UKB), Sigmund-Freud-Str. 25, 53127, Bonn, Germany. glen.kristiansen@ukb.uni-bonn.de.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012008:Recurrence; D012306:Risk; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human
keywords: Immunohistochemistry; Interobserver variation; Prostate cancer; Radical prostatectomy; TRPM4; Tissue biomarker