Universität zu Köln

Heide, Timon, Maurer, Angela, Eipel, Monika, Knoll, Katrin, Geelvink, Mirja, Veeck, Juergen, Knuechel, Ruth, van Essen, Julius, Stoehr, Robert, Hartmann, Arndt, Altmueller, Janine, Graham, Trevor A. and Gaisa, Nadine T. (2019). Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy. J. Pathol., 248 (2). S. 230 - 243. HOBOKEN: WILEY. ISSN 1096-9896

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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 (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heide, Timon UNSPECIFIED UNSPECIFIED UNSPECIFIED Maurer, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Eipel, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Knoll, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Geelvink, Mirja UNSPECIFIED UNSPECIFIED UNSPECIFIED Veeck, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Knuechel, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED van Essen, Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoehr, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Arndt UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Graham, Trevor A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaisa, Nadine T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-147312
DOI:	10.1002/path.5250
Journal or Publication Title:	J. Pathol.
Volume:	248
Number:	2
Page Range:	S. 230 - 243
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1096-9896
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSITIONAL-CELL CARCINOMA; CLONAL EVOLUTION; FGFR3 MUTATIONS; COPY NUMBER; FRAMEWORK; INSIGHTS Multiple languages Oncology; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14731