Departments of Urology and Biochemistry, Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Nat Rev Urol. 2020 May;17(5):259-270. doi: 10.1038/s41585-020-0304-1. Epub 2020 Mar 31.
Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.
尿路上皮癌的组织学和分子分析通常揭示了基因组、转录组和细胞水平上的肿瘤内异质性和肿瘤间异质性。尽管肿瘤是克隆性起始的，但进展和转移通常来自于亚克隆，这些亚克隆可以在自然状态下或治疗过程中发展，从而导致具有异质分布的分子改变。在已经表现出与尿路上皮癌不同形态特征的肿瘤组织中出现的变体组织学是肿瘤异质性的极端例子。最终，异质性导致治疗后耐药和复发，从而导致生存结局不佳。肌肉浸润性和转移性尿路上皮癌患者之间的突变谱差异（患者间异质性）可能导致对化疗和免疫治疗作为一线治疗的反应存在差异。异质性可以在多个层面上发生，对这些改变进行平均化或标准化对于临床试验和药物设计至关重要，以实现适当的治疗靶向。确定异质性的程度可能会影响单药治疗或额外联合治疗的选择，以靶向不同的驱动因素和遗传事件。鉴定致死性肿瘤细胞克隆对于提高尿路上皮癌患者的生存率是必要的。
