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A Long Noncoding RNA-based Classifier for Identifying More Aggressive Low-grade Ta Bladder Cancer with Elevated FGFR3 Activity - Beyond the Abstract

Early bladder cancer, particularly low-grade, stage Ta (TaLG) tumors, is typically considered less aggressive, with higher rates of recurrence, but much lower risk of progression.1 Because recurrence rarely poses immediate harm, management is often conservative, limited to a perioperative intravesical chemotherapy dose followed by surveillance. Patients with additional risk factors (e.g., multifocality, tumor size ≥3 cm) may receive more intensive therapy, yet selecting who truly needs escalation remains challenging using clinical and pathological features alone.

Despite this “low-risk” label, TaLG NMIBC is clinically heterogeneous. A substantial proportion of patients experience frequent recurrences that are not predicted by existing clinicopathologic criteria, leading to repeated procedures, intravesical therapies, and variable management strategies. At present, there are no clinically validated biomarkers that reliably identify which TaLG patients are at greatest risk of recurrence. In this study, we developed a transcriptome-based, single-sample classifier (LC2) using routinely collected TURBT samples, providing a tool suitable for clinical deployment pending further validation.2

Molecular subtyping models applied to NMIBC typically classify most tumors as luminal.3 In MIBC, luminal tumors are often associated with more favorable outcomes, so it is not surprising that NMIBC - which carries a lower overall risk profile - would also fall under this umbrella.4-6 However, luminal disease is not homogeneous, and more granular classifiers have shown that both luminal NMIBC and MIBC can be subdivided into biologically and clinically distinct risk groups.7-9

Many existing molecular models rely on protein-coding transcriptome profiling, which misses a substantial layer of non-coding transcripts that are increasingly recognized as sensitive indicators of tissue or cellular states, and in some cases, markers of specific cancer biology. In bladder cancer, lncRNA profiling can provide this added granularity, separating even otherwise similar luminal tumors into highly resolved clinical subgroups, as illustrated in the present study.2 This approach has now been applied across the spectrum of bladder cancer, from TaLG to high-risk NMIBC (TaHG, T1) and into MIBC.2,8-10

The molecular findings in this study can be integrated with existing clinical risk groupings rather than replacing them. The International Bladder Cancer Group (IBCG) model already stratifies intermediate-risk TaLG patients effectively.11,12 including one recent dataset in which the IBCG criteria cleanly separated high- and lower-risk trajectories.13 LC2 provides an added molecular layer within this framework, offering a way to refine risk assessment even further. In practice, clinicians can continue using familiar IBCG categories while applying LC2 as an additional marker to identify which intermediate-risk TaLG patients may benefit from treatment intensification.

The value of LC2 is that it uncovers clinically meaningful structure within tumors that otherwise appear uniform. Much of the biology driving aggressive behavior in TaLG is not visible through routine pathology or clinical criteria, and LC2 brings that concealed biology into view. By incorporating lncRNA-defined biology into established clinical frameworks such as the IBCG categories, we gain a clearer, more actionable understanding of which patients may benefit from increased surveillance or treatment intensification.

Written by: Ewan A. Gibb, PhD, Senior Research Scientist, Vancouver Prostate Centre; Assistant Professor, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

References:

  1. Matulay JT, Soloway M, Witjes JA, Buckley R, Persad R, Lamm DL, et al. Risk-adapted management of low-grade bladder tumours: recommendations from the International Bladder Cancer Group (IBCG). BJU Int. 2020;125:497-505.
  2. Thu Phung TA, Weng R, Black PC, Dyrskjot L, de Jong JJ, Gibb EA. A Long Noncoding RNA-based Classifier for Identifying More Aggressive Low-grade Ta Bladder Cancer with Elevated FGFR3 Activity. Eur Urol Oncol. 2026.
  3. Meeks JJ, Sjodahl G, Lerner SP, Das A, McConkey DJ, Black PC. Tumor Subtyping: Making Sense of Heterogeneity with a Goal Toward Treatment. Bladder Cancer. 2021;7:1-11.
  4. Kamoun A, de Reynies A, Allory Y, Sjodahl G, Robertson AG, Seiler R, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020;77:420-33.
  5. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017;171:540-56 e25.
  6. Sjodahl G, Eriksson P, Liedberg F, Hoglund M. Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J Pathol. 2017;242:113-25.
  7. de Jong FC, Laajala TD, Hoedemaeker RF, Jordan KR, van der Made ACJ, Boeve ER, et al. Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guerin. Sci Transl Med. 2023;15:eabn4118.
  8. de Jong JJ, Liu Y, Robertson AG, Seiler R, Groeneveld CS, van der Heijden MS, et al. Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis. Genome Med. 2019;11:60.
  9. Lindskrog SV, Prip F, Lamy P, Taber A, Groeneveld CS, Birkenkamp-Demtroder K, et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat Commun. 2021;12:2301.
  10. Weng R, Phung TAT, Bell R, Dyrskjot L, Gibb EA. Long non-coding RNAs define favourable biology in high-risk non-muscle-invasive bladder cancer. BJUI Compass. 2025;6:e70131.
  11. Soria F, Rosazza M, Livoti S, Moschini M, De Angelis M, Del Giudice F, et al. Clinical Validation of the Intermediate-risk Non-muscle-invasive Bladder Cancer Scoring System and Substratification Model Proposed by the International Bladder Cancer Group: A Multicenter Young Academic Urologists Urothelial Working Group Collaboration. Eur Urol Oncol. 2024;7:1497-503.
  12. Tan WS, Steinberg G, Witjes JA, Li R, Shariat SF, Roupret M, et al. Intermediate-risk Non-muscle-invasive Bladder Cancer: Updated Consensus Definition and Management Recommendations from the International Bladder Cancer Group. Eur Urol Oncol. 2022;5:505-16.
  13. Siva JS, Jonnalagadda R, Aydogdu C, et al. Clinical validation of the International Bladder Cancer Group’s intermediate-risk non-muscle-invasive bladder cancer stratification model. Abstract P0204. Presented at: EAU26 - 41st Annual EAU Congress; March 13, 2026; Paris, France.
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