Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts

Anne Sofie Brems-Eskildsen,Cherie Holcomb,Lars Dyrskjøt,Russell Higuchi,Karsten Zieger,Francisco Mansilla,Torben F Ørntoft,Helle Toldbod,Pia P Munksgaard,Michael Borre

doi:10.1186/1471-2407-10-646

Anne Sofie Brems-Eskildsen, Cherie Holcomb + Show 8 more

Open Access

https://doi.org/10.1186/1471-2407-10-646

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Abstract

BackgroundIdentification 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Highlights

Identification of urinary biomarkers for detection of bladder cancer recurrence would be beneficial to minimize the frequency of cystoscopy
Telomerase is inactive in mature cells, telomerase activity can be detected in 85-90% of all primary human cancers [9] and reactivation immortalize cells [10,11,12]. hTERT is described as superior to cytology in regard to sensitivity, but false positive results are seen in benign urothelial conditions [2,7]
SENP1 might function as a marker for tumors in which telomeres were maintained by alternative lengthening of telomeres (ALT), as not all, especially invasive tumors, are hTERT positive [21]

Summary

Introduction

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. Non-muscle invasive bladder cancer is characterized by frequent tumor recurrences. Cystoscopic examinations are unpleasant, time consuming, expensive, and may have serious side effects such as Current FDA approved assays available for bladder cancer detection are: BTA stat, BTA TRAK, NMP22, FDP, Urovysion, and ImmunoCyt. One of the best characterized and more promising biomarkers is telomerase (hTERT) [4,5,6,7,8]. SENP1 might function as a marker for tumors in which telomeres were maintained by ALT, as not all, especially invasive tumors, are hTERT positive [21]

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