Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Nat Commun. 2021 Apr 16;12(1):2301. doi: 10.1038/s41467-021-22465-w.
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
非肌肉浸润性膀胱癌（NMIBC）的分子特征是具有不同临床结局的大生物学异质性。在这里，我们对诊断为 NMIBC 的患者（n=834）进行了综合的多组学分析。转录组分析确定了反映肿瘤生物学和疾病侵袭性的四个类别（1、2a、2b 和 3）。基于转录组的亚分型和染色体不稳定性水平提供了独立的预后价值，超过了既定的预后临床病理参数。高染色体不稳定性、p53 通路破坏和 APOBEC 相关突变与转录组 2a 类和不良预后显著相关。RNA 衍生的免疫细胞浸润与染色体不稳定的肿瘤相关，并在 2b 类中富集。空间蛋白质组学分析证实了 2b 类肿瘤的更高浸润程度，并表明更高的免疫细胞浸润与更低的复发率之间存在关联。最后，使用单个样本分类工具在 1228 个验证样本中证明了转录组类别的独立预后价值。该分类器为生物标志物的发现以及在下一代临床试验中优化治疗和监测提供了框架。
