Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy

Journal article


Publication Details

Author(s): Heide T, Maurer A, Eipel M, Knoll K, Geelvink M, Veeck J, Knuechel R, van Essen J, Stoehr R, Hartmann A, Altmueller J, Graham TA, Gaisa NT
Journal: Journal of Pathology
Publication year: 2019
Volume: 248
Journal issue: 2
Pages range: 230-242
ISSN: 0022-3417


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.


FAU Authors / FAU Editors

Hartmann, Arndt Prof. Dr. med.
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie


External institutions with authors

Queen Mary, University of London
Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen
Universität Köln


How to cite

APA:
Heide, T., Maurer, A., Eipel, M., Knoll, K., Geelvink, M., Veeck, J.,... Gaisa, N.T. (2019). Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy. Journal of Pathology, 248(2), 230-242. https://dx.doi.org/10.1002/path.5250

MLA:
Heide, Timon, et al. "Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy." Journal of Pathology 248.2 (2019): 230-242.

BibTeX: 

Last updated on 2019-03-06 at 11:08

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