Combined miRNA and SERS Urine Liquid Biopsy for the Point-of-Care Diagnosis and Molecular Stratification of Bladder Cancer - Beyond the Abstract

It is no news that one class of molecules alone cannot reach the accuracy required for the clinical implementation of screening by liquid biopsy. Therefore, we combined, for the first time, microRNA profiling and surface-enhanced Raman spectroscopy (SERS) for the diagnosis of bladder cancer on urine samples. In order to mimic a real-life clinical setting, we used a portable Raman spectroscope for the SERS profiling of urine and selected a panel consisting of only three microRNAs that can be measured quickly using quantitative PCR. In addition, all control patients had symptomatology mimicking bladder cancer.

The results showed that the two methods exhibited synergism, increasing the diagnostic accuracy to an area under the curve of 0.92. This made us curious if we could use the same methodology to stratify bladder cancer into low-grade and high-grade tumors as well as to distinguish between the luminal and basal molecular subtypes of bladder cancer. The results were unexpected: while we were indeed able to correctly sub-classify bladder cancer into luminal and basal subtypes using SERS and a panel of two microRNAs, the strategy failed to distinguish between low-grade and high-grade tumors. This provided further evidence that grading itself is only a continuum, reflecting the stage of tumoral evolution, and gives us no insight regarding its intrinsic phenotype. In contrast, basal and luminal subtypes of bladder cancer are true phenotypes and, as we have seen, have different metabolic and microRNA profiles, features that will hopefully lead to their widespread clinical implementation in the near future.

The results are promising, but a rigorous validation is missing. Our strategy will need to be validated in a prospective setting, ideally covering the entire methodological pipeline within one day. Furthermore, as we all know, any liquid biopsy tool for bladder cancer needs to address the ardent problem of detecting recurrence in patients with pre-treated non-muscle invasive tumors. Whether a liquid biopsy tool based on combined microRNA and SERS profiling of urine could successfully detect recurrence and replace cystoscopy for the follow-up of bladder cancer or not, remains currently unknown. Additionally, it would be interesting to see whether SERS and microRNA profiling could be used to select patients with non-muscle invasive bladder cancer that are at high risk of progression and need to undergo upfront cystectomy. Moreover, the emerging and promising data on neoadjuvant intravesical chemotherapy for non-muscle invasive bladder cancer might double the necessity of adequate liquid biopsy with high predictive and prognostic accuracy. However, so far, no strategy seemed to work alone. Our results suggest that maybe it is time to join forces, and use multiple diagnostic tools.

Written by: Mihnea P. Dragomir, MD, PhD,1 Vlad Moisoiu, MD, PhD,2 Tudor Moisoiu, MD, PhD,3

  1. Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Berlin, Germany
  2. Faculty of Physics, Babeș-Bolyai University, Cluj-Napoca, Romania
  3. Clinical Institute of Urology and Renal Transplantation, Cluj-Napoca, Romania

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