| Institution: | 1. Institute of Pathology RWTH Aachen University, Aachen, Germany;2. Department of Urology, University Hospital RWTH Aachen University, Germany;3. Institute of Pathology University Erlangen-Nuernberg, Erlangen, Germany;4. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany;5. Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK |
| Abstract: | We present an evolutionary analysis of the relative time of genetic events underlying tumorigenesis in human bladder cancers from 10 whole cystectomy specimens using multiregional whole-exome sequencing. We timed bladder cancer drivers, mutational signatures, ploidy and copy number alterations, provided evidence for kataegis and correlated alterations with tumour areas and histological phenotypes. We found that: (1) heterogeneous tumour areas/phenotypes had distinct driver mutations, (2) papillary-invasive tumours divided early into two parallel evolving branches and (3) parallel evolution of subclonal driver mutations occurred. APOBEC mutational signatures were found to be very early events, active in carcinoma in situ, and often remained a dominant source of mutations throughout tumour evolution. Genetic progression from carcinoma in situ followed driver mutations in NA13/FAT1, ZBTB7B or EP300/USP28/KMT2D. Our results point towards a more diverse mutational trajectory of bladder tumorigenesis and underpin the importance of timing of mutational processes and clonal architecture in bladder cancer as important aspects for successful prognostication and therapy. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
