title: Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts.
abstract: BACKGROUND
  Identification of urinary biomarkers for detection of bladder cancer recurrence would be beneficial to minimize the frequency of cystoscopy. Our objective was to determine the usability of urine content of mRNA in the detection and prediction of bladder cancer recurrence.
  
  
  METHODS
  We analyzed 123 prospectively cross-sectional collected urine samples from 117 patients with bladder cancer (12 incident cancers and 111 control visits). We used biopsies from cystoscopies as diagnostic criteria for recurrence, and followed the patients for a median time of 28.5 months (range 0-44 months). We measured the levels of hTERT, SENP1, PPP1CA, and MCM5 mRNA in urine by q-RT- PCR.
  
  
  RESULTS
  We found significant differences in urinary content of hTERT (p < 0.001), SENP1 (p < 0.001), MCM5 (p < 0.001), and PPP1CA (p < 0.001) transcripts, when comparing urine samples from patients with and without tumor present in the bladder. We obtained sensitivity and specificity values for hTERT: 63/73, SENP1: 56/78, MCM5: 63/66, and PPP1CA: 69/63, respectively. Including follow-up data resulted in sensitivity and specificity values for hTERT: 62/84, SENP1:53/84, MCM5: 61/73, and PPP1CA: 65/66. Interestingly, at non-tumor visits the urinary content of especially hTERT (p = 0.0001) and MCM5 (p = 0.02) were significantly associated with subsequent tumour recurrence. Combining the markers with cytology improved the detection. The best combination was hTERT and cytology with a sensitivity of 71% and a specificity of 86% after follow-up. Further prospective validation or registration studies needs to be carried out before clinical use.
  
  
  CONCLUSIONS
  We could use the urinary content of hTERT, SENP1, PPP1CA, and MCM5 to detect bladder cancer recurrence. All markers showed a higher sensitivity than cytology. The detection rate improved when including cytology results, but also the combination of hTERT and MCM5 increased the detection rate. Furthermore, hTERT and MCM5 levels predicted subsequent tumor recurrences.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Skejby, Denmark.
authors.forename: Anne Sofie
authors.initials: AS
authors.lastname: Brems-Eskildsen
authors.forename: Karsten
authors.initials: K
authors.lastname: Zieger
authors.forename: Helle
authors.initials: H
authors.lastname: Toldbod
authors.forename: Cherie
authors.initials: C
authors.lastname: Holcomb
authors.forename: Russell
authors.initials: R
authors.lastname: Higuchi
authors.forename: Francisco
authors.initials: F
authors.lastname: Mansilla
authors.forename: Pia P
authors.initials: PP
authors.lastname: Munksgaard
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D018797:Cell Cycle Proteins / Q000235:genetics*; D003430:Cross-Sectional Studies; D003546:Cysteine Endopeptidases; D003558:Cystoscopy; D003718:Denmark; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D054645:Protein Phosphatase 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000652:urine*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D019098:Telomerase / Q000235:genetics*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000652:urine
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C489423:MCM5 protein, human; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase; C517187:PPP1CA protein, human; D054645:Protein Phosphatase 1; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases