MicroRNA As Prognostic And Diagnostic Biomarker In Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis

Dany Muhammad Daffa; Abdan Syakura Danil; Raihan Syarif Humaidy; Besut Daryanto

doi:10.11594/bjurology.2025.006.02.2

Authors

Dany Muhammad Daffa Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia, 45363
Abdan Syakura Danil Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia, 45363
Raihan Syarif Humaidy Faculty of Medicine, Universitas Muhammadiyah Surabaya, Pertamina Hospital, Balikpapan, East Kalimantan, Indonesia, 60113
Besut Daryanto Department of Urology, Faculty of Medicine, Universitas Brawijaya, Dr. Saiful Anwar General Hospital, Malang, East Java, Indonesia, 57112

DOI:

https://doi.org/10.11594/bjurology.2025.006.02.2

Keywords:

biomarker, diagnostic, microRNA, prognostic, upper tract urothelial carcinoma

Abstract

Introduction. Upper tract urothelial carcinoma (UTUC) is a relatively rare but aggressive form of cancer that affects the urinary system. Early detection and accurate prognosis are critical for improving patient outcomes. Recent studies suggest that microRNAs, small non-coding RNA molecules, may serve as potential biomarkers for various cancers, including UTUC. This systematic review and meta-analysis aim to evaluate the effectiveness of microRNAs as prognostic and diagnostic tools in UTUC.

Methods. We searched PubMed and EuropePMC for studies published until December 2024 and performed a meta-analysis using RevMan 5.4 and MetaDisc.

Results. The review included a total of 6 studies, encompassing data from over 300 sample patients. Our analysis confirmed that specific microRNAs are significantly associated with both the presence and progression of UTUC. MicroRNAs demonstrated significant prognostic outcomes, such as progression-free survival (3.72; 95% CI: 2.46-5.62; p < 0.00001) and cancer-specific survival (3.46; 95% CI: 1.68-7.15; p = 0.0008). These biomarkers showed high sensitivity (0.75; 95% CI: 0.72-0.78; p = 0.0000) and specificity (0.82; 95% CI: 0.79-0.85; p = 0.0000), with the following diagnostic indices Positive Likelihood Ratio (PLR) (4.45, 95% CI: 3.22-6.14), Negative Likelihood Ratio (NLR) (0.31, 95% CI: 0.24-0.39), Diagnostic Odds Ratio (DOR) (18.04, 95% CI: 10.46-31.14), and Area Under Curve (AUC) 0.86 in the diagnosis of UTUC. Subgroup analysis of diagnostic studies based on countries revealed higher results in Asian countries. MicroRNAs showed significant associations with UTUC progression and survival, with high diagnostic accuracy (AUC 0.86).

Conclusion. MicroRNA could be used as potential diagnostic and prognostic biomarkers in UTUC.

Keywords: biomarker, diagnostic, microRNA, prognostic, upper tract urothelial carcinoma

References

Wang P, Wang L, Du J, Liang G. Chromophobe renal cell carcinoma with ipsilateral ureteral urothelial carcinoma: A case report. Mol Clin Oncol. 2023;18(4):30; doi: 10.3892/mco.2023.2626.

Bitaraf M, Yazdi G, Amini M. Upper Tract Urothelial Carcinoma (UTUC) Diagnosis and Risk Stratification: A Comprehensive Review. Cancers (Basel).2023; Oct 1;15(20):4987. doi: 10.3390/cancers15204987.

Luo Z, Jiao B, Su C, Zhao H, Yan Y, Pan Y, et al. Correlation between the timing of diagnostic ureteroscopy for upper tract urothelial cancer and intravesical recurrence after radical nephroureterectomy. Front Oncol. 2023;13:1122877; doi: 10.3389/fonc.2023.1122877.

Annese T, Tamma R, De Giorgis M, Ribatti D. MicroRNAs biogenesis, functions and role in tumor angiogenesis. Front Oncol. 2020;10:581007; doi: 10.3389/fonc.2020.581007.

Lee J, Mulder F, Leeflang M, Wolff R, Whiting P, Bossuyt PM. QUAPAS: An adaptation of the QUADAS-2 tool to assess Prognostic Accuracy Studies. Ann Intern Med. 2022;175(7):1010–1018; doi: 10.7326/M22-0276.

Schütz V, Nessler CL, Duensing A, Zschäbitz S, Jäger D, Debus J, et al. Improved survival of patients with newly diagnosed oligometastatic prostate cancer through intensified multimodal treatment. Front Oncol. 2024;14:1475914; doi: 10.3389/fonc.2024.1475914.

Shreffler J, Huecker MR. Diagnostic Testing Accuracy: Sensitivity, Specificity, Predictive Values and Likelihood Ratios. In: StatPearls StatPearls Publishing: Treasure Island (FL); 2025.

Chang Y, Phillips MR, Guymer RH, Thabane L, Bhandari M, Chaudhary V, et al. The 5 min meta-analysis: understanding how to read and interpret a forest plot. EYE. 2022;36(4):673–675; doi: 10.1038/s41433-021-01867-6.

Montalbo R, Izquierdo L, Ingelmo-Torres M, Lozano JJ, Capitán D, Alcaraz A, et al. Prognostic value of circulating microRNAs in upper tract urinary carcinoma. Oncotarget. 2018;9(24):16691–16700; doi: 10.18632/oncotarget.24672.

Izquierdo L, Ingelmo-Torres M, Mallofré C, Lozano JJ, Verhasselt-Crinquette M, Leroy X, et al. Prognostic value of microRNA expression pattern in upper tract urothelial carcinoma. BJU Int. 2014;113(5):813–821; doi: 10.1111/bju.12551.

Izquierdo L, Montalbo R, Ingelmo-Torres M, Mallofré C, Ramírez-Backhaus M, Rubio J, et al. Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study. Oncotarget. 2017;8(31):51522–51529; doi: 10.18632/oncotarget.17884.

Urabe F, Matsuzaki J, Takeshita F, Kishida T, Ochiya T, Hirai K. Independent verification of circulating miRNA as diagnostic biomarkers for urothelial carcinoma. Cancer Sci. 2022;113(10):3510–3517; doi: 10.1111/cas.15496.

Tao J, Yang X, Li P, Wei J, Deng X, Cheng Y, et al. Identification of circulating microRNA signatures for upper tract urothelial carcinoma detection. Mol Med Rep. 2015;12(5):6752–6760; doi: 10.3892/mmr.2015.4257.

Kriebel S, Schmidt D, Holdenrieder S, Goltz D, Kristiansen G, Moritz R, et al. Analysis of tissue and serum microRNA expression in patients with upper urinary tract urothelial cancer. PLoS One. 2015;10(1):e0117284; doi: 10.1371/journal.pone.0117284.

Subiela JD, Territo A, Mercadé A, Balañà J, Aumatell J, Calderon J, et al. Diagnostic accuracy of ureteroscopic biopsy in predicting stage and grade at final pathology in upper tract urothelial carcinoma: Systematic review and meta-analysis. Eur J Surg Oncol. 2020;46(11):1989–1997; doi: 10.1016/j.ejso.2020.06.024.

Cinque A, Capasso A, Vago R, Floris M, Lee MW, Minnei R, et al. MicroRNA signatures in the upper urinary tract urothelial carcinoma scenario: Ready for the game changer? Int J Mol Sci. 2022;23(5):2602; doi: 10.3390/ijms23052602.

Tsikitas LA, Hopstone MD, Raman A, Duddalwar V. Imaging in Upper Tract urothelial carcinoma: A review. Cancers (Basel). 2023;15(20); doi: 10.3390/cancers15205040.

Egger V, Hutterer GC, Mischinger J, Seles M, Pichler R, Mannweiler S, et al. Preoperative fibrinogen/CRP score predicts survival in upper urothelial tract carcinoma patients undergoing radical curative surgery. World J Urol. 2023;41(5):1359–1364; doi: 10.1007/s00345-023-04379-y.

Schuettfort VM, Pradere B, Trinh QD, D'Andrea D, Quhal F, Mostafaei H, et al. Impact of preoperative plasma levels of interleukin 6 and interleukin 6 soluble receptors on disease outcomes after radical cystectomy for bladder cancer. Cancer Immunol Immunother. 2022;71(1):85–95; doi: 10.1007/s00262-021-02953-0.

Mamdouh S, Sherif H, Romeih M, Elesaily K. Urine micro-RNA signature as a potential non-invasive diagnostic biomarker in bladder cancer. Asian Pac J Cancer Prev. 2023;24(1):121–131; doi: 10.31557/APJCP.2023.24.1.121.

Liu P, Wang K, Li J, Ogasawara MA, Xia Z, Wierda WG, et al. Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations. Haematologica. 2024;109(2):479–492; doi: 10.3324/haematol.2023.283181.

Huang YC, Wang HJ, Sung MT, Chuang YC, Chen YT, Cheng YT, et al. The lowest level of tumor involvement is a significant prognostic factor for upper tract urothelial carcinoma after radical nephroureterectomy: A large retrospective cohort study. Front Oncol. 2022;12. doi: 10.3389/fonc.2022.1031774. eCollection 2022.

White SJ, Phua QS, Lu L, Yaxley KL, McInnes MDF, To MS. Heterogeneity in systematic reviews of medical imaging diagnostic test accuracy studies: A systematic review. JAMA Netw Open. 2024;7(2):e240649; doi: 10.1001/jamanetworkopen.2024.0649.