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ARTICLE

The AR-ADAR2-PD-L1 Axis as a Prognostic Biomarker System in BCG-Treated High-Grade Papillary Urothelial Carcinoma: A Single-Center Retrospective Cohort Study

Gabriele Ricciardi1,2,*, Mariagiovanna Ballato1, Pietro Tralongo1,*, Marta Rossanese3, Ludovica Pepe1,4, Antonio Ieni4, Guido Fadda4, Vincenzo Ficarra5, Vincenzo Fiorentino1,4, Francesco Pierconti6, Maurizio Martini4
1 Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy
2 Istituto Clinico Polispecialistico C.O.T. Cure Ortopediche Traumatologiche s.p.a., Messina, Italy
3 Department of Human Pathology of Adults and Developmental Age “Gaetano Barresi”, Division of Urology, University of Messina, Messina, Italy
4 Department of Human Pathology of Adults and Developmental Age “Gaetano Barresi”, Division of Pathology, University of Messina, Messina, Italy
5 Department of Clinical and Experimental Medicine, Division of Urology, University of Messina, Messina, Italy
6 Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
* Corresponding Author: Gabriele Ricciardi. Email: email; Pietro Tralongo. Email: email

Oncology Research https://doi.org/10.32604/or.2026.086237

Received 28 May 2026; Accepted 10 September 2026; Published online 20 September 2026

Abstract

Background: High-grade papillary urothelial carcinoma (HG-PUC) represents a high-risk non-muscle-invasive bladder cancer with frequent recurrence after intravesical Bacillus Calmette-Guérin (BCG) therapy, and reliable prognostic biomarkers remain lacking. The aim of this study was to evaluate the prognostic significance of the androgen receptor (AR)-ADAR2-programmed death-ligand 1 (PD-L1) axis in BCG-treated HG-PUC. Methods: A single-center retrospective cohort of 146 patients with HG-PUC treated with transurethral resection followed by intravesical BCG was evaluated. AR, ADAR2, PD-L1, CD4, and CD8 expression were evaluated by immunohistochemistry. miR-200a-3p and interferon-γ (IFN-γ) transcript expression were assessed by quantitative PCR in an exploratory subgroup of 40 patients. Associations between molecular markers, clinicopathological variables, and Recurrence-Free Survival were assessed. Results: High AR expression was significantly associated with reduced ADAR2 expression, increased PD-L1 expression, higher CD4/CD8 ratios, and shorter RFS (all p < 0.0001). AR, ADAR2, and PD-L1 remained independent prognostic factors for RFS in multivariable analysis, and their combined model showed good prognostic discrimination (Harrell’s C-index = 0.792, 95% CI 0.754–0.830). During a median follow-up of 10 months (95% CI, 9–12), 52 RFS events occurred. In the exploratory cohort, tumors with low AR and high ADAR2 expression exhibited significantly higher miR-200a-3p and IFN-γ transcript levels. Conclusions: The AR-ADAR2-PD-L1 molecular profile was independently associated with RFS in patients with BCG-treated HG-PUC. These findings support its potential role in prognostic risk stratification, although prospective external validation and functional studies are required before clinical implementation.

Keywords

Androgen receptor; ADAR2; high-grade papillary urothelial carcinoma; BCG treatment; non-muscle-invasive bladder cancer; miR-200a-3p; PD-L1

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