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Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients

A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and...

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Autores principales: Menzel, Michael, Ossowski, Stephan, Kral, Sebastian, Metzger, Patrick, Horak, Peter, Marienfeld, Ralf, Boerries, Melanie, Wolter, Steffen, Ball, Markus, Neumann, Olaf, Armeanu-Ebinger, Sorin, Schroeder, Christopher, Matysiak, Uta, Goldschmid, Hannah, Schipperges, Vincent, Fürstberger, Axel, Allgäuer, Michael, Eberhardt, Timo, Niewöhner, Jakob, Blaumeiser, Andreas, Ploeger, Carolin, Haack, Tobias Bernd, Tay, Timothy Kwang Yong, Kelemen, Olga, Pauli, Thomas, Kirchner, Martina, Kluck, Klaus, Ott, Alexander, Renner, Marcus, Admard, Jakob, Gschwind, Axel, Lassmann, Silke, Kestler, Hans, Fend, Falko, Illert, Anna Lena, Werner, Martin, Möller, Peter, Seufferlein, Thomas Theodor Werner, Malek, Nisar, Schirmacher, Peter, Fröhling, Stefan, Kazdal, Daniel, Budczies, Jan, Stenzinger, Albrecht
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589320/
https://www.ncbi.nlm.nih.gov/pubmed/37864096
http://dx.doi.org/10.1038/s41698-023-00457-x
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author Menzel, Michael
Ossowski, Stephan
Kral, Sebastian
Metzger, Patrick
Horak, Peter
Marienfeld, Ralf
Boerries, Melanie
Wolter, Steffen
Ball, Markus
Neumann, Olaf
Armeanu-Ebinger, Sorin
Schroeder, Christopher
Matysiak, Uta
Goldschmid, Hannah
Schipperges, Vincent
Fürstberger, Axel
Allgäuer, Michael
Eberhardt, Timo
Niewöhner, Jakob
Blaumeiser, Andreas
Ploeger, Carolin
Haack, Tobias Bernd
Tay, Timothy Kwang Yong
Kelemen, Olga
Pauli, Thomas
Kirchner, Martina
Kluck, Klaus
Ott, Alexander
Renner, Marcus
Admard, Jakob
Gschwind, Axel
Lassmann, Silke
Kestler, Hans
Fend, Falko
Illert, Anna Lena
Werner, Martin
Möller, Peter
Seufferlein, Thomas Theodor Werner
Malek, Nisar
Schirmacher, Peter
Fröhling, Stefan
Kazdal, Daniel
Budczies, Jan
Stenzinger, Albrecht
author_facet Menzel, Michael
Ossowski, Stephan
Kral, Sebastian
Metzger, Patrick
Horak, Peter
Marienfeld, Ralf
Boerries, Melanie
Wolter, Steffen
Ball, Markus
Neumann, Olaf
Armeanu-Ebinger, Sorin
Schroeder, Christopher
Matysiak, Uta
Goldschmid, Hannah
Schipperges, Vincent
Fürstberger, Axel
Allgäuer, Michael
Eberhardt, Timo
Niewöhner, Jakob
Blaumeiser, Andreas
Ploeger, Carolin
Haack, Tobias Bernd
Tay, Timothy Kwang Yong
Kelemen, Olga
Pauli, Thomas
Kirchner, Martina
Kluck, Klaus
Ott, Alexander
Renner, Marcus
Admard, Jakob
Gschwind, Axel
Lassmann, Silke
Kestler, Hans
Fend, Falko
Illert, Anna Lena
Werner, Martin
Möller, Peter
Seufferlein, Thomas Theodor Werner
Malek, Nisar
Schirmacher, Peter
Fröhling, Stefan
Kazdal, Daniel
Budczies, Jan
Stenzinger, Albrecht
author_sort Menzel, Michael
collection PubMed
description A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79–1, TMB: 0.97–0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.
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spelling pubmed-105893202023-10-22 Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients Menzel, Michael Ossowski, Stephan Kral, Sebastian Metzger, Patrick Horak, Peter Marienfeld, Ralf Boerries, Melanie Wolter, Steffen Ball, Markus Neumann, Olaf Armeanu-Ebinger, Sorin Schroeder, Christopher Matysiak, Uta Goldschmid, Hannah Schipperges, Vincent Fürstberger, Axel Allgäuer, Michael Eberhardt, Timo Niewöhner, Jakob Blaumeiser, Andreas Ploeger, Carolin Haack, Tobias Bernd Tay, Timothy Kwang Yong Kelemen, Olga Pauli, Thomas Kirchner, Martina Kluck, Klaus Ott, Alexander Renner, Marcus Admard, Jakob Gschwind, Axel Lassmann, Silke Kestler, Hans Fend, Falko Illert, Anna Lena Werner, Martin Möller, Peter Seufferlein, Thomas Theodor Werner Malek, Nisar Schirmacher, Peter Fröhling, Stefan Kazdal, Daniel Budczies, Jan Stenzinger, Albrecht NPJ Precis Oncol Article A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79–1, TMB: 0.97–0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization. Nature Publishing Group UK 2023-10-20 /pmc/articles/PMC10589320/ /pubmed/37864096 http://dx.doi.org/10.1038/s41698-023-00457-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Menzel, Michael
Ossowski, Stephan
Kral, Sebastian
Metzger, Patrick
Horak, Peter
Marienfeld, Ralf
Boerries, Melanie
Wolter, Steffen
Ball, Markus
Neumann, Olaf
Armeanu-Ebinger, Sorin
Schroeder, Christopher
Matysiak, Uta
Goldschmid, Hannah
Schipperges, Vincent
Fürstberger, Axel
Allgäuer, Michael
Eberhardt, Timo
Niewöhner, Jakob
Blaumeiser, Andreas
Ploeger, Carolin
Haack, Tobias Bernd
Tay, Timothy Kwang Yong
Kelemen, Olga
Pauli, Thomas
Kirchner, Martina
Kluck, Klaus
Ott, Alexander
Renner, Marcus
Admard, Jakob
Gschwind, Axel
Lassmann, Silke
Kestler, Hans
Fend, Falko
Illert, Anna Lena
Werner, Martin
Möller, Peter
Seufferlein, Thomas Theodor Werner
Malek, Nisar
Schirmacher, Peter
Fröhling, Stefan
Kazdal, Daniel
Budczies, Jan
Stenzinger, Albrecht
Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title_full Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title_fullStr Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title_full_unstemmed Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title_short Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
title_sort multicentric pilot study to standardize clinical whole exome sequencing (wes) for cancer patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589320/
https://www.ncbi.nlm.nih.gov/pubmed/37864096
http://dx.doi.org/10.1038/s41698-023-00457-x
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