YAP1 activation is associated with the progression and response to immunotherapy of non-muscle invasive bladder cancer

EBioMedicine. 2022 Jul;81:104092. doi: 10.1016/j.ebiom.2022.104092. Epub 2022 Jun 2.


Background: Despite the availability of several treatments for non-muscle-invasive bladder cancer (NMIBC), many patients are still not responsive to treatments, and the disease progresses. A new prognostic classifier can differentiate between treatment response and progression, and it could be used as a very important tool in patient decision-making regarding treatment options. In this study, we focused on the activation of Yes-associated protein 1 (YAP1), which is known to play a pivotal role in tumour progression and serves as a factor contributing to the mechanism of resistance to various relevant therapeutic agents. We further evaluated its potential as a novel prognostic agent.

Methods: We identified YAP1-associated gene signatures based on UC3-siYAP1 cells (n=8) and NMIBC cohort (n=460). Cross-validation was performed using 5 independent bladder cancer patient cohorts (n=1006). We also experimentally validated the changes of gene expression levels representing each subgroup.

Findings: The 976-gene signature based on YAP1-activation redefined three subgroups and had the benefits of Bacillus Calmette-Guérin (BCG) treatment in patients with NMIBC (hazard ratio 3.32, 95% CI 1.29-8.56, p = 0.01). The integrated analysis revealed that YAP1 activation was associated with the characterization of patients with high-risk NMIBC and the response to immunotherapy.

Interpretation: This study suggests that YAP1 activation has an important prognostic effect on bladder cancer progression and might be useful in the selection of immunotherapy.

Funding: A funding list that contributed to this research can be found in the Acknowledgements section.

Keywords: Bacillus Calmette-Guérin (BCG); Immunotherapy; Non-muscle-invasive bladder cancer (NMIBC); Prognosis; YAP1.

MeSH terms

  • Adjuvants, Immunologic
  • BCG Vaccine
  • Humans
  • Immunologic Factors / therapeutic use
  • Immunotherapy
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / drug therapy
  • Prognosis
  • Urinary Bladder Neoplasms* / drug therapy
  • Urinary Bladder Neoplasms* / therapy
  • YAP-Signaling Proteins


  • Adjuvants, Immunologic
  • BCG Vaccine
  • Immunologic Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human