Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
Department of Biomedical Sciences, Dong-A University, Busan 49315, Republic of Korea.
EBioMedicine. 2022 Jul;81:104092. doi: 10.1016/j.ebiom.2022.104092. Epub 2022 Jun 2.
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.
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.
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.
This study suggests that YAP1 activation has an important prognostic effect on bladder cancer progression and might be useful in the selection of immunotherapy.
A funding list that contributed to this research can be found in the Acknowledgements section.
尽管有多种治疗非肌肉浸润性膀胱癌（NMIBC）的方法，但许多患者对治疗仍无反应，且疾病仍在进展。一种新的预后分类器可以区分治疗反应和进展，它可以作为患者在治疗选择方面决策的重要工具。在这项研究中，我们专注于 Yes 相关蛋白 1（YAP1）的激活，YAP1 已知在肿瘤进展中起关键作用，并作为对各种相关治疗药物产生耐药性的机制中的一个因素。我们进一步评估了其作为一种新的预后标志物的潜力。
我们基于 UC3-siYAP1 细胞（n=8）和 NMIBC 队列（n=460）确定了 YAP1 相关基因特征。使用 5 个独立的膀胱癌患者队列（n=1006）进行了交叉验证。我们还通过实验验证了代表每个亚组的基因表达水平变化。
基于 YAP1 激活的 976 个基因特征重新定义了三个亚组，并对 NMIBC 患者的卡介苗（BCG）治疗有获益（危险比 3.32，95%置信区间 1.29-8.56，p=0.01）。综合分析表明，YAP1 激活与高危 NMIBC 患者的特征和免疫治疗反应相关。
本研究表明 YAP1 激活对膀胱癌的进展有重要的预后影响，可能对免疫治疗的选择有用。
资助本研究的资金清单可在致谢部分找到。
