Low-grade, stage Ta (TaLG) non-muscle-invasive bladder cancer (NMIBC) is generally nonaggressive; yet, some patients experience recurrence or progression. We previously identified long noncoding RNA cluster 2 (LC2) as an aggressive TaLG subgroup via consensus clustering, which required a cohort-level analysis.
We developed a single-sample transcriptome classifier for patient-level LC2 identification.
Using the UROMOL cohort (n = 276) for training/testing and the Hurst (Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight. Cell Rep Med 2021;2:100472) cohort (n = 72) for validation, we performed feature selection via median absolute deviation and nested cross-validation. An elastic net regression model (α = 0.5) was trained using ten-fold cross-validation. Performance was evaluated through a pathway analysis, with prognostic significance assessed by Kaplan-Meier and univariable Cox regression.
Biological characterization revealed that LC2 tumors exhibited higher proliferation (G2M/E2F signatures), elevated FGFR3 pathway activity, and reduced sonic hedgehog signaling and immune activity (p < 0.001). The classifier identified 7/72 LC2 tumors in the Hurst cohort. LC2-TaLG patients had significantly worse recurrence-free survival (log-rank p < 0.001). On univariable Cox regression analysis, LC2 status was strongly associated with recurrence (hazard ratio 4.52, 95% confidence interval 1.78-11.5; p = 0.001). LC2-predicted tumors in the Hurst cohort showed similar biological patterns.
We developed a single-sample transcriptomic classifier identifying aggressive TaLG NMIBC, demonstrating reproducibility across platforms. If validated, this model has the potential to support clinical decision-making.
European urology oncology. 2026 Feb 27 [Epub ahead of print]
Tran Anh Thu Phung, Rachel Weng, Peter C Black, Lars Dyrskjøt, Joep J de Jong, Ewan A Gibb
Vancouver Prostate Centre, M. H. Mohseni Institute of Urologic Sciences, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands., Vancouver Prostate Centre, M. H. Mohseni Institute of Urologic Sciences, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41763905