Genetic alterations identified in adjacent normal appearing tissue in bladder cancer patients are indicative of a field disease. Here we assessed normal urothelium transformation and intra-tumour heterogeneity (ITH) in four patients with bladder cancer. Exome sequencing identified private acquired mutations in a lymph node metastasis and local recurrences. Deep re-sequencing revealed presence of at least three and four subclones in two patients with multifocal disease, while no demarcation of subclones was identified in the two patients with unifocal disease. Analysis of adjacent normal urothelium showed low frequency mutations in patients with multifocal disease. Expression profiling showed intra-tumour and intra-patient co-existence of basal- and luminal-like tumour regions, and patients with multifocal disease had a greater degree of genomic and transcriptomic ITH, as well as transformation of adjacent normal cells, compared to patients with unifocal disease. Analysis of the adjacent urothelium may pave the way for therapies targeting the field disease.

中文翻译：

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膀胱癌分子异质性的全面多区域分析。

在膀胱癌患者的相邻正常出现组织中鉴定出的遗传改变预示着田间疾病。在这里，我们评估了四名膀胱癌患者的正常尿路上皮转化和肿瘤内异质性（ITH）。外显子组测序确定了淋巴结转移和局部复发中的私人获得性突变。深度重测序显示两名多灶性疾病患者中至少存在三个和四个亚克隆，而在两名单灶性疾病患者中未鉴定出亚克隆的界限。对邻近正常尿道上皮的分析显示，多灶性疾病患者存在低频突变。表达谱显示肿瘤内和患者内共存在基底样和管腔样肿瘤区域，与单灶性疾病患者相比，多灶性疾病患者的基因组和转录组ITH以及相邻正常细胞的转化程度更高。对相邻尿道上皮的分析可能为针对田间疾病的疗法铺平道路。