Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.

以顺铂为基础的化疗过度治疗是肌层浸润性膀胱癌（MIBC）治疗中的一个主要问题，目前尚未在临床上应用已报道的用于预测反应的生物标志物。在这里，我们对 300 名接受化疗（新辅助或一线）治疗的 MIBC 患者进行了全面的多组学分析（基因组学、转录组学、表观基因组学和蛋白质组学），以确定与治疗反应相关的分子变化。基于 DNA 的反应关联集中于由大量染色体改变、插入缺失、特征 5 突变和/或BRCA2突变驱动的基因组不稳定性。表达数据确定了与不良反应相关的基底/鳞状基因表达亚型。免疫细胞浸润和高 PD-1 蛋白表达与治疗反应相关。通过整合基因组和转录组数据，我们将患者分层为基于顺铂的反应可能性低和高的组。这可以为未来在前瞻性临床试验验证后的患者选择铺平道路。