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TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers

Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations ar...

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Autores principales: Weyerer, Veronika, Eckstein, Markus, Strissel, Pamela L., Wullweber, Adrian, Lange, Fabienne, Tögel, Lars, Geppert, Carol I., Sikic, Danijel, Taubert, Helge, Wach, Sven, Wullich, Bernd, Hartmann, Arndt, Stoehr, Robert, Giedl, Johannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915609/
https://www.ncbi.nlm.nih.gov/pubmed/33562516
http://dx.doi.org/10.3390/genes12020230
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author Weyerer, Veronika
Eckstein, Markus
Strissel, Pamela L.
Wullweber, Adrian
Lange, Fabienne
Tögel, Lars
Geppert, Carol I.
Sikic, Danijel
Taubert, Helge
Wach, Sven
Wullich, Bernd
Hartmann, Arndt
Stoehr, Robert
Giedl, Johannes
author_facet Weyerer, Veronika
Eckstein, Markus
Strissel, Pamela L.
Wullweber, Adrian
Lange, Fabienne
Tögel, Lars
Geppert, Carol I.
Sikic, Danijel
Taubert, Helge
Wach, Sven
Wullich, Bernd
Hartmann, Arndt
Stoehr, Robert
Giedl, Johannes
author_sort Weyerer, Veronika
collection PubMed
description Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.
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spelling pubmed-79156092021-03-01 TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers Weyerer, Veronika Eckstein, Markus Strissel, Pamela L. Wullweber, Adrian Lange, Fabienne Tögel, Lars Geppert, Carol I. Sikic, Danijel Taubert, Helge Wach, Sven Wullich, Bernd Hartmann, Arndt Stoehr, Robert Giedl, Johannes Genes (Basel) Article Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development. MDPI 2021-02-05 /pmc/articles/PMC7915609/ /pubmed/33562516 http://dx.doi.org/10.3390/genes12020230 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Weyerer, Veronika
Eckstein, Markus
Strissel, Pamela L.
Wullweber, Adrian
Lange, Fabienne
Tögel, Lars
Geppert, Carol I.
Sikic, Danijel
Taubert, Helge
Wach, Sven
Wullich, Bernd
Hartmann, Arndt
Stoehr, Robert
Giedl, Johannes
TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title_full TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title_fullStr TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title_full_unstemmed TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title_short TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
title_sort tert promoter mutation analysis of whole-organ mapping bladder cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915609/
https://www.ncbi.nlm.nih.gov/pubmed/33562516
http://dx.doi.org/10.3390/genes12020230
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