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Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes.
Nature Reviews Urology ( IF 12.1 ) Pub Date : 2020-03-31 , DOI: 10.1038/s41585-020-0304-1 Joshua J Meeks 1 , Hikmat Al-Ahmadie 2 , Bishoy M Faltas 3 , John A Taylor 4 , Thomas W Flaig 5 , David J DeGraff 6 , Emil Christensen 7 , Benjamin L Woolbright 4 , David J McConkey 8 , Lars Dyrskjøt 7
Nature Reviews Urology ( IF 12.1 ) Pub Date : 2020-03-31 , DOI: 10.1038/s41585-020-0304-1 Joshua J Meeks 1 , Hikmat Al-Ahmadie 2 , Bishoy M Faltas 3 , John A Taylor 4 , Thomas W Flaig 5 , David J DeGraff 6 , Emil Christensen 7 , Benjamin L Woolbright 4 , David J McConkey 8 , Lars Dyrskjøt 7
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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.
中文翻译：
膀胱癌的基因组异质性：挑战和改善结果的可能解决方案。
尿路上皮癌的组织学和分子分析通常揭示基因组、转录和细胞水平上的肿瘤内和肿瘤间异质性。尽管肿瘤是克隆起始的，但进展和转移通常是由自然或治疗过程中形成的亚克隆引起的，导致具有异质分布的分子改变。肿瘤组织中的变异组织学已发展出与尿路上皮癌不同的不同形态特征，这是肿瘤异质性的极端例子。最终，异质性会导致耐药性和治疗后复发，导致生存结果不佳。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）可能导致一线治疗化疗和免疫疗法反应的差异。异质性可能发生在多个层面，平均或标准化这些改变对于临床试验和药物设计以实现适当的治疗目标至关重要。异质性程度的识别可能会影响单一疗法或额外组合疗法的选择，以针对不同的驱动因素和遗传事件。为了提高尿路上皮癌患者的生存率，需要鉴定致命的肿瘤细胞克隆。
更新日期：2020-03-31
中文翻译：
膀胱癌的基因组异质性：挑战和改善结果的可能解决方案。
尿路上皮癌的组织学和分子分析通常揭示基因组、转录和细胞水平上的肿瘤内和肿瘤间异质性。尽管肿瘤是克隆起始的，但进展和转移通常是由自然或治疗过程中形成的亚克隆引起的，导致具有异质分布的分子改变。肿瘤组织中的变异组织学已发展出与尿路上皮癌不同的不同形态特征，这是肿瘤异质性的极端例子。最终，异质性会导致耐药性和治疗后复发，导致生存结果不佳。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）可能导致一线治疗化疗和免疫疗法反应的差异。异质性可能发生在多个层面，平均或标准化这些改变对于临床试验和药物设计以实现适当的治疗目标至关重要。异质性程度的识别可能会影响单一疗法或额外组合疗法的选择，以针对不同的驱动因素和遗传事件。为了提高尿路上皮癌患者的生存率，需要鉴定致命的肿瘤细胞克隆。
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