Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular biomarkers of progression in non-muscle-invasive bladder cancer — beyond conventional risk stratification

Nature Reviews Urology (2024)Cite this article

Subjects

Abstract

The global incidence of bladder cancer is more than half a million diagnoses each year. Bladder cancer can be categorized into non-muscle-invasive bladder cancer (NMIBC), which accounts for ~75% of diagnoses, and muscle-invasive bladder cancer (MIBC). Up to 45% of patients with NMIBC develop disease progression to MIBC, which is associated with a poor outcome, highlighting a clinical need to identify these patients. Current risk stratification has a prognostic value, but relies solely on clinicopathological parameters that might not fully capture the complexity of disease progression. Molecular research has led to identification of multiple crucial players involved in NMIBC progression. Identified biomarkers of progression are related to cell cycle, MAPK pathways, apoptosis, tumour microenvironment, chromatin stability and DNA-damage response. However, none of these biomarkers has been prospectively validated. Reported gene signatures of progression do not improve NMIBC risk stratification. Molecular subtypes of NMIBC have improved our understanding of NMIBC progression, but these subtypes are currently unsuitable for clinical implementation owing to a lack of prospective validation, limited predictive value as a result of intratumour subtype heterogeneity, technical challenges, costs and turnaround time. Future steps include the development of consensus molecular NMIBC subtypes that might improve conventional clinicopathological risk stratification. Prospective implementation studies of biomarkers and the design of biomarker-guided clinical trials are required for the integration of molecular biomarkers into clinical practice.

Key points

  • A thorough understanding of molecular mechanisms that drive disease progression is crucial to improve non-muscle invasive bladder cancer (NMIBC) risk stratification.

  • Independent genomic and transcriptomic biomarkers of progression have been reported and hold the potential to improve risk stratification, but lack prospective validation.

  • One gene signature of progression (12-gene PCR panel) was prospectively validated, but this signature did not improve conventional risk stratification.

  • Transcriptomic molecular subtyping could be a strategy for predicting NMIBC progression and might also provide molecular targets for precision medicine approaches.

  • Future investigations should explore mechanisms underlying NMIBC progression after BCG treatment, as the current guideline-recommended treatment for patients with BCG-unresponsive tumours is a radical cystectomy, but a subset of patients might be candidates for alternative bladder-sparing therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of genes and mechanisms associated with progressive disease in non-muscle-invasive bladder cancer.
Fig. 2: Transcriptomic subtypes in non-muscle invasive bladder cancer.

Similar content being viewed by others

References

  1. Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229–263 (2024).

    Article  PubMed  Google Scholar 

  2. Saginala, K. et al. Epidemiology of bladder cancer. Med. Sci. 8, 15 (2020).

    CAS  Google Scholar 

  3. Sylvester, R. J. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 49, 466–475; discussion 475–477 (2006).

    Article  PubMed  Google Scholar 

  4. Babjuk, M. et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur. Urol. 81, 75–94 (2022).

    Article  PubMed  Google Scholar 

  5. Ge, P. et al. Oncological outcome of primary and secondary muscle-invasive bladder cancer: a systematic review and meta-analysis. Sci. Rep. 8, 7543 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  6. D’Andrea, D. et al. The impact of primary versus secondary muscle-invasive bladder cancer at diagnosis on the response to neoadjuvant chemotherapy. Eur. Urol. Open. Sci. 41, 74–80 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pones, M. et al. Differential prognosis and response of denovo vs. secondary muscle-invasive bladder cancer: an updated systematic review and meta-analysis. Cancers 13, 2496 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mossanen, M. et al. Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories. World J. Urol. 37, 2059–2065 (2019).

    Article  PubMed  Google Scholar 

  9. Fernandez-Gomez, J. et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J. Urol. 182, 2195–2203 (2009).

    Article  PubMed  Google Scholar 

  10. Chang, S. S. et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J. Urol. 196, 1021–1029 (2016).

    Article  PubMed  Google Scholar 

  11. Soukup, V. et al. Prognostic performance and reproducibility of the 1973 and 2004/2016 World Health Organization grading classification systems in non-muscle-invasive bladder cancer: a European Association of Urology non-muscle invasive bladder cancer guidelines panel systematic review. Eur. Urol. 72, 801–813 (2017).

    Article  PubMed  Google Scholar 

  12. Cambier, S. et al. EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1–3 years of maintenance bacillus Calmette-Guerin. Eur. Urol. 69, 60–69 (2016).

    Article  PubMed  Google Scholar 

  13. Rieken, M. et al. Comparison of the EORTC tables and the EAU categories for risk stratification of patients with nonmuscle-invasive bladder cancer. Urol. Oncol. 36, 8.e17–8.e24 (2018).

    Article  PubMed  Google Scholar 

  14. Krajewski, W. et al. Accuracy of the CUETO, EORTC 2016 and EAU 2021 scoring models and risk stratification tables to predict outcomes in high-grade non-muscle-invasive urothelial bladder cancer. Urol. Oncol. 40, 491.e11–491.e19 (2022).

    Article  CAS  PubMed  Google Scholar 

  15. Lobo, N. et al. Updated European Association of Urology (EAU) prognostic factor risk groups overestimate the risk of progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin. Eur. Urol. Oncol. 5, 84–91 (2022).

    Article  PubMed  Google Scholar 

  16. Guerrero-Ramos, F. et al. Predicting recurrence and progression in patients with non-muscle-invasive bladder cancer: systematic review on the performance of risk stratification models. Bladder Cancer 8, 339–357 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Soukup, V. et al. Risk stratification tools and prognostic models in non-muscle-invasive bladder cancer: a critical assessment from the European Association of Urology non-muscle-invasive bladder cancer guidelines panel. Eur. Urol. Focus. 6, 479–489 (2020).

    Article  PubMed  Google Scholar 

  18. Jobczyk, M., Stawiski, K., Fendler, W. & Rozanski, W. Validation of EORTC, CUETO, and EAU risk stratification in prediction of recurrence, progression, and death of patients with initially non-muscle-invasive bladder cancer (NMIBC): a cohort analysis. Cancer Med. 9, 4014–4025 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cordon-Cardo, C. et al. Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J. Natl Cancer Inst. 84, 1251–1256 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Sarkis, A. S. et al. Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J. Natl Cancer Inst. 85, 53–59 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Casadevall, D., Kilian, A. Y. & Bellmunt, J. The prognostic role of epigenetic dysregulation in bladder cancer: a systematic review. Cancer Treat. Rev. 61, 82–93 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Birkenkamp-Demtroder, K. et al. Genomic alterations in liquid biopsies from patients with bladder cancer. Eur. Urol. 70, 75–82 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. De Carlo, C., Valeri, M., Corbitt, D. N., Cieri, M. & Colombo, P. Non-muscle invasive bladder cancer biomarkers beyond morphology. Front. Oncol. 12, 947446 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Pepe, M. S. et al. Phases of biomarker development for early detection of cancer. J. Natl Cancer Inst. 93, 1054–1061 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Liu, J., Peng, Y. & Wei, W. Cell cycle on the crossroad of tumorigenesis and cancer therapy. Trends Cell Biol. 32, 30–44 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Hurst, C. D. et al. Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight. Cell Rep. Med. 2, 100472 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mitra, A. P., Birkhahn, M. & Cote, R. J. p53 and retinoblastoma pathways in bladder cancer. World J. Urol. 25, 563–571 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Sjodahl, G. et al. Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma. Int. J. Cancer 146, 2636–2647 (2020).

    Article  PubMed  Google Scholar 

  29. Gatti, V., Fierro, C., Annicchiarico-Petruzzelli, M., Melino, G. & Peschiaroli, A. DeltaNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment. Mol. Oncol. 13, 981–1001 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Choi, W. et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25, 152–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Papadimitriou, M. A. et al. DeltaNp63 transcript loss in bladder cancer constitutes an independent molecular predictor of TaT1 patients post-treatment relapse and progression. J. Cancer Res. Clin. Oncol. 145, 3075–3087 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Urist, M. J. et al. Loss of p63 expression is associated with tumor progression in bladder cancer. Am. J. Pathol. 161, 1199–1206 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gaya, J. M. et al. ΔNp63 expression is a protective factor of progression in clinical high grade T1 bladder cancer. J. Urol. 193, 1144–1150 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Khan, F. M. et al. Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures. Nat. Commun. 8, 198 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mun, J. Y. et al. E2F1 promotes progression of bladder cancer by modulating rad54l involved in homologous recombination repair. Int. J. Mol. Sci. 21, 9025 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Robertson, A. G. et al. Identification of differential tumor subtypes of T1 bladder cancer. Eur. Urol. 78, 533–537 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Lee, J. S. et al. Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors. J. Clin. Oncol. 28, 2660–2667 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Song, B.-N. et al. Identification of an immunotherapy-responsive molecular subtype of bladder cancer. eBioMedicine 50, 238–245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim, S. K. et al. A molecular signature determines the prognostic and therapeutic subtype of non-muscle-invasive bladder cancer responsive to intravesical bacillus Calmette-Guerin therapy. Int. J. Mol. Sci. 22, 1450 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Feber, A. et al. Amplification and overexpression of E2F3 in human bladder cancer. Oncogene 23, 1627–1630 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Oeggerli, M. et al. E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene 23, 5616–5623 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Hurst, C. D., Tomlinson, D. C., Williams, S. V., Platt, F. M. & Knowles, M. A. Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification. Oncogene 27, 2716–2727 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Cheng, C., Varn, F. S. & Marsit, C. J. E2F4 program is predictive of progression and intravesical immunotherapy efficacy in bladder cancer. Mol. Cancer Res. 13, 1316–1324 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lindskrog, S. V. et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 12, 2301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ramesh, N. et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor-armed oncolytic adenovirus for the treatment of bladder cancer. Clin. Cancer Res. 12, 305–313 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Packiam, V. T. et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol. Oncol. 36, 440–447 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04452591 (2024).

  48. Fagundes, R. & Teixeira, L. K. Cyclin E/CDK2: DNA replication, replication stress and genomic instability. Front. Cell Dev. Biol. 9, 774845 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhao, H. et al. Prognostic values of CCNE1 amplification and overexpression in cancer patients: a systematic review and meta-analysis. J. Cancer 9, 2397–2407 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Bellmunt, J. et al. Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer. Cancer Res. 80, 4476–4486 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bacon, J. V. W. et al. Somatic features of response and relapse in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin immunotherapy. Eur. Urol. Oncol. 5, 677–686 (2022).

    Article  PubMed  Google Scholar 

  52. Song, B. N., Kim, S. K. & Chu, I. S. Bioinformatic identification of prognostic signature defined by copy number alteration and expression of CCNE1 in non-muscle invasive bladder cancer. Exp. Mol. Med. 49, e282 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Le Goux, C. et al. Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer. Sci. Rep. 10, 16641 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wee, S. et al. Discovery of INCB123667, a potent and selective cyclin-dependent kinase 2 (CDK2) inhibitor for the treatment of cyclin E dysregulated cancers. Eur. J. Cancer 174, S79 (2022).

    Article  Google Scholar 

  55. Wang, Y. Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors. J. Clin. Oncol. 41, e17546–e17546 (2023).

    Article  Google Scholar 

  56. Beck, H. et al. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol. Cell Biol. 32, 4226–4236 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aarts, M. et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2, 524–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Mir, S. E. et al. In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell 18, 244–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Murakami, K. et al. Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer. Cancer Sci. 112, 3669–3681 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fu, S. et al. Multicenter phase II trial of the WEE1 inhibitor adavosertib in refractory solid tumors harboring CCNE1 amplification. J. Clin. Oncol. 41, 1725–1734 (2023).

    Article  CAS  PubMed  Google Scholar 

  61. Goel, S., Bergholz, J. S. & Zhao, J. J. Targeting CDK4 and CDK6 in cancer. Nat. Rev. Cancer 22, 356–372 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhao, R., Choi, B. Y., Lee, M. H., Bode, A. M. & Dong, Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine 8, 30–39 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Bartlett, J. M. et al. Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? Br. J. Cancer 77, 2193–2198 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tsukamoto, M. et al. Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence. Cancer Genet. Cytogenet. 134, 41–45 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Meeks, J. J. et al. Genomic characterization of high-risk non-muscle invasive bladder cancer. Oncotarget 7, 75176–75184 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Jung, I. et al. Chromosome 9 monosomy by fluorescence in situ hybridization of bladder irrigation specimens is predictive of tumor recurrence. J. Urol. 162, 1900–1903 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Rebouissou, S. et al. CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J. Pathol. 227, 315–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Ploussard, G. et al. The prognostic value of FGFR3 mutational status for disease recurrence and progression depends on allelic losses at 9p22. Am. J. Cancer Res. 1, 498–507 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Breyer, J. et al. High CDKN2A/p16 and low FGFR3 expression predict progressive potential of stage pT1 urothelial bladder carcinoma. Clin. Genitourin. Cancer 16, 248–256.e2 (2018).

    Article  PubMed  Google Scholar 

  70. Sikic, D. et al. The prognostic value of FGFR3 expression in patients with T1 non-muscle invasive bladder cancer. Cancer Manag. Res. 13, 6567–6578 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Rubio, C. et al. CDK4/6 inhibitor as a novel therapeutic approach for advanced bladder cancer independently of RB1 status. Clin. Cancer Res. 25, 390–402 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03837821 (2024).

  73. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04887831 (2024).

  74. Solomon, D. A. et al. Frequent truncating mutations of STAG2 in bladder cancer. Nat. Genet. 45, 1428–1430 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Balbas-Martinez, C. et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat. Genet. 45, 1464–1469 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Taylor, C. F., Platt, F. M., Hurst, C. D., Thygesen, H. H. & Knowles, M. A. Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes. Hum. Mol. Genet. 23, 1964–1974 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Pietzak, E. J. et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur. Urol. 72, 952–959 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Shao, Y. et al. Prognostic factors of non-muscle invasive bladder cancer: a study based on next-generation sequencing. Cancer Cell Int. 21, 23 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gordon, N. S. et al. STAG2 protein expression in non-muscle-invasive bladder cancer: associations with sex, genomic and transcriptomic changes, and clinical outcomes. Eur. Urol. Open. Sci. 38, 88–95 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Taber, A. et al. STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer. Urol. Oncol. 39, 438.e1–438.e9 (2021).

    Article  CAS  PubMed  Google Scholar 

  81. Lelo, A. et al. STAG2 is a biomarker for prediction of recurrence and progression in papillary non-muscle-invasive bladder cancer. Clin. Cancer Res. 24, 4145–4153 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rinaldetti, S. et al. FOXM1 predicts disease progression in non-muscle invasive bladder cancer. J. Cancer Res. Clin. Oncol. 144, 1701–1709 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Breyer, J. et al. FOXM1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT1 non-muscle-invasive bladder cancer. BJU Int. 123, 187–196 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Shi, J., Zhang, P., Liu, L., Min, X. & Xiao, Y. Weighted gene coexpression network analysis identifies a new biomarker of CENPF for prediction disease prognosis and progression in nonmuscle invasive bladder cancer. Mol. Genet. Genom. Med. 7, e982 (2019).

    Article  CAS  Google Scholar 

  85. Lin, S. C. et al. Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat. Commun. 7, 11418 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Aytes, A. et al. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25, 638–651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Khan, M. A., Khan, P., Ahmad, A., Fatima, M. & Nasser, M. W. FOXM1: a small fox that makes more tracks for cancer progression and metastasis. Semin. Cancer Biol. 92, 1–15 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jeyaprakash, A. A. et al. Structural and functional organization of the Ska complex, a key component of the kinetochore-microtubule interface. Mol. Cell 46, 274–286 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Gaitanos, T. N. et al. Stable kinetochore-microtubule interactions depend on the Ska complex and its new component Ska3/C13Orf3. EMBO J. 28, 1442–1452 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li, J. et al. SKA1 over-expression promotes centriole over-duplication, centrosome amplification and prostate tumourigenesis. J. Pathol. 234, 178–189 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Jiang, S. et al. High expression of spindle and kinetochore-associated protein 1 predicts early recurrence and progression of non-muscle invasive bladder cancer. Cancer Biomark. 22, 543–549 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Li, Z. et al. Immunological role and prognostic value of the SKA family in pan-cancer analysis. Front. Immunol. 14, 1012999 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lan, H. et al. Pancancer analysis of SKA1 mutation and its association with the diagnosis and prognosis of human cancers. Genomics 115, 110554 (2023).

    Article  CAS  PubMed  Google Scholar 

  94. Wang, C. et al. SKA3 is a prognostic biomarker and associated with immune infiltration in bladder cancer. Hereditas 159, 20 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. You, C., Piao, X. M., Kang, K., Kim, Y. J. & Kang, K. Integrative transcriptome profiling reveals SKA3 as a novel prognostic marker in non-muscle invasive bladder cancer. Cancers 13, 4673 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dhillon, A. S., Hagan, S., Rath, O. & Kolch, W. MAP kinase signalling pathways in cancer. Oncogene 26, 3279–3290 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Katoh, M. & Nakagama, H. FGF receptors: cancer biology and therapeutics. Med. Res. Rev. 34, 280–300 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Hernandez, S. et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J. Clin. Oncol. 24, 3664–3671 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. van Rhijn, B. W. et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur. Urol. 58, 433–441 (2010).

    Article  PubMed  Google Scholar 

  100. Burger, M. et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur. Urol. 54, 835–843 (2008).

    Article  PubMed  Google Scholar 

  101. van Rhijn, B. W. et al. The FGFR3 mutation is related to favorable pT1 bladder cancer. J. Urol. 187, 310–314 (2012).

    Article  PubMed  Google Scholar 

  102. van Rhijn, B. W. G. et al. FGFR3 mutation status and FGFR3 expression in a large bladder cancer cohort treated by radical cystectomy: implications for anti-FGFR3 treatment?(†). Eur. Urol. 78, 682–687 (2020).

    Article  PubMed  Google Scholar 

  103. van Rhijn, B. W. et al. FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res. 64, 1911–1914 (2004).

    Article  PubMed  Google Scholar 

  104. Kang, H. W. et al. Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status. Oncol. Lett. 14, 3817–3824 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  105. van Kessel, K. E. M. et al. Molecular markers increase precision of the European Association of Urology non-muscle-invasive bladder cancer progression risk groups. Clin. Cancer Res. 24, 1586–1593 (2018).

    Article  PubMed  Google Scholar 

  106. Ascione, C. M. et al. Role of FGFR3 in bladder cancer: treatment landscape and future challenges. Cancer Treat. Rev. 115, 102530 (2023).

    Article  CAS  PubMed  Google Scholar 

  107. Siefker-Radtke, A. O. et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 23, 248–258 (2022).

    Article  CAS  PubMed  Google Scholar 

  108. Catto, J. W. F. et al. Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer. Ann. Oncol. 35, 98–106 (2024).

    Article  CAS  PubMed  Google Scholar 

  109. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03914794 (2024).

  110. Moasser, M. M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26, 6469–6487 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhao, J. et al. Prognostic role of HER2 expression in bladder cancer: a systematic review and meta-analysis. Int. Urol. Nephrol. 47, 87–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Breyer, J. et al. ERBB2 expression as potential risk-stratification for early cystectomy in patients with pT1 bladder cancer and concomitant carcinoma in situ. Urol. Int. 98, 282–289 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Lim, S. D. et al. Clinical significance of substaging and HER2 expression in papillary nonmuscle invasive urothelial cancers of the urinary bladder. J. Korean Med. Sci. 30, 1068–1077 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tan, X. et al. Prognostic significance of HER2 expression in patients with bacillus Calmette-Guérin-exposed non-muscle-invasive bladder cancer. Eur. Urol. Oncol. https://doi.org/10.1016/j.euo.2023.10.003 (2023).

  115. Kocsmár, I. et al. Addition of chromosome 17 polysomy and HER2 amplification status improves the accuracy of clinicopathological factor-based progression risk stratification and tumor grading of non-muscle-invasive bladder cancer. Cancers 14, 4570 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Koshkin, V. S., O’Donnell, P., Yu, E. Y. & Grivas, P. Systematic review: targeting HER2 in bladder cancer. Bladder Cancer 5, 1–12 (2019).

    Article  Google Scholar 

  117. Copeland-Halperin, R. S., Liu, J. E. & Yu, A. F. Cardiotoxicity of HER2-targeted therapies. Curr. Opin. Cardiol. 34, 451–458 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Swain, S. M., Shastry, M. & Hamilton, E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug. Discov. 22, 101–126 (2023).

    Article  CAS  PubMed  Google Scholar 

  119. Peters, S. et al. Antibody-drug conjugates in lung and breast cancer: current evidence and future directions — a position statement from the ETOP IBCSG Partners Foundation. Ann. Oncol. 35, 607–629 (2024).

    Article  CAS  PubMed  Google Scholar 

  120. Sheng, X. et al. Efficacy and safety of disitamab vedotin in patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic urothelial carcinoma: a combined analysis of two phase II clinical trials. J. Clin. Oncol. 42, 1391–1402 (2024).

    Article  CAS  PubMed  Google Scholar 

  121. Sheng, X. et al. Open-label, multicenter, phase II study of RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma. Clin. Cancer Res. 27, 43–51 (2021).

    Article  CAS  PubMed  Google Scholar 

  122. Matt, D. G. et al. Primary analysis from DS8201-A-U105: a phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). J. Clin. Oncol. 40, 438–438 (2022).

    Article  Google Scholar 

  123. Shih, C. H., Lin, Y. H., Luo, H. L. & Sung, W. W. Antibody-drug conjugates targeting HER2 for the treatment of urothelial carcinoma: potential therapies for HER2-positive urothelial carcinoma. Front. Pharmacol. 15, 1326296 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zerenturk, E. J., Sharpe, L. J., Ikonen, E. & Brown, A. J. Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. Prog. Lipid Res. 52, 666–680 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Luu, W. et al. Signaling regulates activity of DHCR24, the final enzyme in cholesterol synthesis. J. Lipid Res. 55, 410–420 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lee, G. T. et al. DHCR24 is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma, and its functional role is involved in the aggressive properties of urothelial carcinoma cells. Ann. Surg. Oncol. 21, S538–S545 (2014).

    Article  PubMed  Google Scholar 

  127. Liu, X. P. et al. DHCR24 predicts poor clinicopathological features of patients with bladder cancer: a STROBE-compliant study. Medicine 97, e11830 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Korner, A. et al. Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proc. Natl Acad. Sci. USA 116, 20623–20634 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wu, J. et al. Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation. Br. J. Cancer 123, 1673–1685 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fang, J., Akaike, T. & Maeda, H. Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment. Apoptosis 9, 27–35 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Kim, W. J. et al. Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer. Mol. Cancer 9, 3 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Yim, M.-S. et al. HMOX1 is an important prognostic indicator of nonmuscle invasive bladder cancer recurrence and progression. J. Urol. 185, 701–705 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Peng, Y. et al. JUND-dependent up-regulation of HMOX1 is associated with cisplatin resistance in muscle-invasive bladder cancer. J. Biochem. 168, 73–82 (2020).

    Article  CAS  PubMed  Google Scholar 

  134. Miyata, Y., Kanda, S., Mitsunari, K., Asai, A. & Sakai, H. Heme oxygenase-1 expression is associated with tumor aggressiveness and outcomes in patients with bladder cancer: a correlation with smoking intensity. Transl. Res. 164, 468–476 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Matsuo, T. et al. Pathological significance and prognostic implications of heme oxygenase 1 expression in non-muscle-invasive bladder cancer: correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX-2. Oncol. Lett. 13, 275–280 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Berberat, P. O. et al. Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment. Clin. Cancer Res. 11, 3790–3798 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Zhe, N. et al. Heme oxygenase-1 plays a crucial role in chemoresistance in acute myeloid leukemia. Hematology 20, 384–391 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Podkalicka, P., Mucha, O., Jozkowicz, A., Dulak, J. & Loboda, A. Heme oxygenase inhibition in cancers: possible tools and targets. Contemp. Oncol. 22, 23–32 (2018).

    Google Scholar 

  139. Alfano, M. et al. The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat. Rev. Urol. 13, 77–90 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Strandgaard, T. et al. Elevated T-cell exhaustion and urinary tumor DNA levels are associated with bacillus Calmette-Guerin failure in patients with non-muscle-invasive bladder cancer. Eur. Urol. 82, 646–656 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Inman, B. A. et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109, 1499–1505 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Lee, Y. C. et al. The dynamic roles of the bladder tumour microenvironment. Nat. Rev. Urol. 19, 515–533 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Nakanishi, J. et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56, 1173–1182 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Le Goux, C. et al. Correlation between messenger RNA expression and protein expression of immune checkpoint-associated molecules in bladder urothelial carcinoma: a retrospective study. Urol. Oncol. 35, 257–263 (2017).

    Article  PubMed  Google Scholar 

  146. Taber, A. et al. Immune contexture and differentiation features predict outcome in bladder cancer. Eur. Urol. Oncol. 5, 203–213 (2022).

    Article  PubMed  Google Scholar 

  147. Breyer, J. et al. High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients. Cancer Immunol. Immunother. 67, 403–412 (2018).

    Article  CAS  PubMed  Google Scholar 

  148. Kawahara, T. et al. PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer. BMC Urol. 18, 97 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Huang, Y. et al. The prognostic significance of PD-L1 in bladder cancer. Oncol. Rep. 33, 3075–3084 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Nowak, Ł., Krajewski, W., Poterek, A., Śliwa, A. & Zdrojowy, R. The prognostic value of programmed cell death protein ligand 1 in patients with non-muscle-invasive bladder cancer treated with bacille Calmette–Guérin immunotherapy: current status. Arab. J. Urol. 19, 67–70 (2021).

    Article  Google Scholar 

  151. Balar, A. V. et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 22, 919–930 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Andrea, N. et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): results from cohort B of the phase 2 KEYNOTE-057 trial. J. Clin. Oncol. 41, LBA442–LBA442 (2023).

    Article  Google Scholar 

  153. Black, P. C. et al. Phase 2 trial of atezolizumab in bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive bladder cancer: SWOG S1605. Eur. Urol. 84, 536–544 (2023).

    Article  CAS  PubMed  Google Scholar 

  154. Hahn, N. M. et al. A phase 1 trial of durvalumab in combination with bacillus Calmette-Guerin (BCG) or external beam radiation therapy in patients with BCG-unresponsive non-muscle-invasive bladder cancer: the Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER study. Eur. Urol. 83, 486–494 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Li, R. et al. A phase II study of durvalumab for bacillus Calmette-Guerin (BCG) unresponsive urothelial carcinoma in situ of the bladder. Clin. Cancer Res. 29, 3875–3881 (2023).

    Article  CAS  PubMed  Google Scholar 

  156. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03528694 (2024).

  157. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05943106 (2024).

  158. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03892642 (2024).

  159. de Jong, F. C., Rutten, V. C., Zuiverloon, T. C. M. & Theodorescu, D. Improving anti-PD-1/PD-L1 therapy for localized bladder cancer. Int. J. Mol. Sci. 22, 2800 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Hannouneh, Z. A. et al. Novel immunotherapeutic options for BCG-unresponsive high-risk non-muscle-invasive bladder cancer. Cancer Med. 12, 21944–21968 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hazini, A., Fisher, K. & Seymour, L. Deregulation of HLA-I in cancer and its central importance for immunotherapy. J. Immunother. Cancer 9, e002899 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Aptsiauri, N. & Garrido, F. The challenges of HLA class I loss in cancer immunotherapy: facts and hopes. Clin. Cancer Res. 28, 5021–5029 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Gil-Julio, H. et al. Tumor escape phenotype in bladder cancer is associated with loss of HLA class I expression, T-cell exclusion and stromal changes. Int. J. Mol. Sci. 22, 7248 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yi, R. et al. MHC-II signature correlates with anti-tumor immunity and predicts anti-PD-L1 response of bladder cancer. Front. Cell Dev. Biol. 10, 757137 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Piao, X. M. et al. A prognostic immune predictor, HLA-DRA, plays diverse roles in non-muscle invasive and muscle invasive bladder cancer. Urol. Oncol. 39, 237.e21–237.e29 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. de Jong, F. C. et al. Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guerin. Sci. Transl. Med. 15, eabn4118 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Brabletz, S., Schuhwerk, H., Brabletz, T. & Stemmler, M. P. Dynamic EMT: a multi-tool for tumor progression. EMBO J. 40, e108647 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Banerjee, S. et al. Multiple roles for basement membrane proteins in cancer progression and EMT. Eur. J. Cell Biol. 101, 151220 (2022).

    Article  CAS  PubMed  Google Scholar 

  169. Zhu, H., Chen, H., Wang, J., Zhou, L. & Liu, S. Collagen stiffness promoted non-muscle-invasive bladder cancer progression to muscle-invasive bladder cancer. Onco Targets Ther. 12, 3441–3457 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Brooks, M. et al. Positive association of collagen type I with non-muscle invasive bladder cancer progression. Oncotarget 7, 82609–82619 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Tsai, M. C. et al. DDR2 overexpression in urothelial carcinoma indicates an unfavorable prognosis: a large cohort study. Oncotarget 7, 78918–78931 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Cyrenne, J. B. et al. Comprehensive gene sequencing to identify progression predictors to muscle-invasive bladder cancer. J. Clin. Oncol. 41, 570–570 (2023).

    Article  Google Scholar 

  173. Chen, Z. et al. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11, 5077 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wang, L. et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat. Commun. 9, 3503 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Tu, M. M. et al. Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. Sci. Adv. 5, eaav2437 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. You, S. et al. Discoidin domain receptor-driven gene signatures as markers of patient response to anti-PD-L1 immune checkpoint therapy. J. Natl Cancer Inst. 114, 1380–1391 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Nassar, A. H. et al. Mutational analysis of 472 urothelial carcinoma across grades and anatomic sites. Clin. Cancer Res. 25, 2458–2470 (2019).

    Article  PubMed  Google Scholar 

  179. Bakr, A. et al. ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response. Nucleic Acids Res. 52, 5698–5719 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Balbas-Martinez, C. et al. ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors. PLoS ONE 8, e62483 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Strandgaard, T. et al. Field cancerization is associated with tumor development, T-cell exhaustion, and clinical outcomes in bladder cancer. Eur. Urol. 85, 82–92 (2023).

    Article  PubMed  Google Scholar 

  182. Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020).

    Article  CAS  PubMed  Google Scholar 

  183. Bastos, D. A. et al. Genomic biomarkers and underlying mechanism of benefit from BCG immunotherapy in non-muscle invasive bladder cancer. Bladder Cancer 6, 171–186 (2020).

    Article  Google Scholar 

  184. Mandal, J., Mandal, P., Wang, T.-L. & Shih, I.-M. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response. J. Biomed. Sci. 29, 71 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Marteijn, J. A., Lans, H., Vermeulen, W. & Hoeijmakers, J. H. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol. 15, 465–481 (2014).

    Article  CAS  PubMed  Google Scholar 

  186. Kim, J. et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat. Genet. 48, 600–606 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Li, Q. et al. ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer. Clin. Cancer Res. 25, 977–988 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Wang, F., Dong, X., Yang, F. & Xing, N. Comparative analysis of differentially mutated genes in non-muscle and muscle-invasive bladder cancer in the Chinese population by whole exome sequencing. Front. Genet. 13, 831146 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Maas, M., Todenhöfer, T. & Black, P. C. Urine biomarkers in bladder cancer — current status and future perspectives. Nat. Rev. Urol. 20, 597–614 (2023).

    Article  PubMed  Google Scholar 

  190. Kang, H. W. et al. Long-term validation of a molecular progression-associated gene classifier for prediction of muscle invasion in primary non-muscle-invasive bladder cancer. Oncol. Lett. 14, 2468–2474 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Kang, H. W. et al. Molecular progression risk score for prediction of muscle invasion in primary T1 high-grade bladder cancer. Clin. Genitourin. Cancer 16, 274–280 (2018).

    Article  PubMed  Google Scholar 

  192. Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).

    Article  CAS  PubMed  Google Scholar 

  193. Baek, S.-W. et al. YAP1 activation is associated with the progression and response to immunotherapy of non-muscle invasive bladder cancer. eBioMedicine 81, 104092 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Dyrskjot, L. et al. Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR. Br. J. Cancer 107, 1392–1398 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Dyrskjot, L. et al. Prognostic impact of a 12-gene progression score in non-muscle-invasive bladder cancer: a prospective multicentre validation study. Eur. Urol. 72, 461–469 (2017).

    Article  PubMed  Google Scholar 

  196. Seiler, R. et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur. Urol. 72, 544–554 (2017).

    Article  CAS  PubMed  Google Scholar 

  197. Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556 e25 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Sjodahl, G. et al. A molecular taxonomy for urothelial carcinoma. Clin. Cancer Res. 18, 3377–3386 (2012).

    Article  PubMed  Google Scholar 

  199. Marzouka, N. A. et al. A validation and extended description of the Lund taxonomy for urothelial carcinoma using the TCGA cohort. Sci. Rep. 8, 3737 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Sjodahl, G., Eriksson, P., Liedberg, F. & Hoglund, M. Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J. Pathol. 242, 113–125 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Marzouka, N. A. et al. The Lund molecular taxonomy applied to non-muscle-invasive urothelial carcinoma. J. Mol. Diagn. 24, 992–1008 (2022).

    Article  CAS  PubMed  Google Scholar 

  202. Aramendía Cotillas, E. et al. A versatile and upgraded version of the LundTax classification algorithm applied to independent cohorts. Preprint at bioRxiv https://doi.org/10.1101/2023.12.15.571519v1 (2023).

  203. Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  204. Goel, A. et al. Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes. Genome Med. 14, 59 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Erasmus Urology Research. IMPASSE-trial: improved patient stratification by molecular subtyping of high-risk non-muscle invasive bladder cancer and identification of novel treatments by ex vivo medium-throughput drug screening. Erasmus Urology Research https://www.erasmusurologyresearch.nl/impasse-trial/ (2024).

  206. Meeks, J. J. et al. Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes. Nat. Rev. Urol. 17, 259–270 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Lindskrog, S. V. et al. Single-nucleus and spatially resolved intratumor subtype heterogeneity in bladder cancer. Eur. Urol. Open Sci. 51, 78–88 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank S. Meertens-Gunput, M. Udo and C. Niehot from the Erasmus MC Medical Library for their assistance in the literature search, and F. Khoraminia for conceptualizing figures.

Author information

Author notes

  1. These authors contributed equally: Mitchell Olislagers, Florus C. de Jong.

Authors and Affiliations

  1. Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

    Mitchell Olislagers, Florus C. de Jong, Vera C. Rutten, Joost L. Boormans, Tokameh Mahmoudi & Tahlita C. M. Zuiverloon

  2. Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands

    Tokameh Mahmoudi

Authors
  1. Mitchell Olislagers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florus C. de Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vera C. Rutten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joost L. Boormans
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tokameh Mahmoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tahlita C. M. Zuiverloon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.O., F.C.D.J. and V.C.R. researched data for the article. T.C.M.Z., M.O. and F.C.D.J. contributed substantially to discussion of the content. M.O. and F.C.D.J. wrote the article. T.C.M.Z., M.O., F.C.D.J., J.L.B. and T.M. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Tahlita C. M. Zuiverloon.

Ethics declarations

Competing interests

T.M. has a research collaboration with HUB Organoids, Gilead and Viiv. J.L.B. receives consultancy fees (all paid to Erasmus MC) from Janssen, BMS, AstraZeneca, Merck AG/Pfizer, MSD and Bayer. He also has research collaborations with Merck AG/Pfizer, MSD, Janssen, and VitroScan and has done book writing for Astellas. T.C.M.Z. has research collaborations with Vitroscan, HUB Organoids and Valar Labs. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Lars Dyrskjøt, who co-reviewed with Trine Strandgaard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Olislagers, M., de Jong, F.C., Rutten, V.C. et al. Molecular biomarkers of progression in non-muscle-invasive bladder cancer — beyond conventional risk stratification. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00914-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41585-024-00914-7

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer