Abstract
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.
Highlights
Bladder cancer is a common malignant disease, and is the cause of 165.000 cancer related deaths annually[1]
Studies analysing the adjacent normal appearing urothelium have revealed that the urothelium is highly affected by the disease, harbouring genetic alterations shared with the tumours[15,16,17,18]
DNA was extracted from 17 tumour samples and from leucocytes procured from four patients with advanced bladder cancer, treated with radical cystectomy and lymphadenectomy
Summary
Bladder cancer is a common malignant disease, and is the cause of 165.000 cancer related deaths annually[1]. The field disease and clonal relationship between tumours could be caused by intraepithelial migration and/or luminal seeding and implantation of carcinoma cells from existing tumours - eventually giving rise to recurrent tumours. To investigate the level of ITH in bladder cancer, and to analyse the extend of mutations observed in adjacent normal urothelial cells we performed multi-regional whole exome sequencing (WES). This was followed by deep targeted sequencing of multiple laser micro-dissected (LMD) cells from tumour regions and normal biopsies from four patients with advanced bladder cancer. We observed multiple tumour specific mutations at low frequencies in the adjacent normal samples
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