Multicentric pilot study to standardize clinical whole exome sequencing (WES) for cancer patients
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Date
2023-10-20
Authors
Menzel, Michael
Ossowski, Stephan
Kral, Sebastian
Metzger, Patrick
Horak, Peter
Marienfeld, Ralf
Boerries, Melanie
Wolter, Steffen
Ball, Markus
Neumann, Olaf
Journal Title
Journal ISSN
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Publication Type
Wissenschaftlicher Artikel
Published in
npj Precision Oncology, 2023
Abstract
Abstract
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.
Description
Faculties
Medizinische Fakultät
Institutions
Institut für Medizinische Systembiologie
Zentrum für personalisierte Medizin
UKU. Institut für Pathologie
UKU. Klinik für Innere Medizin I
Zentrum für personalisierte Medizin
UKU. Institut für Pathologie
UKU. Klinik für Innere Medizin I
Citation
DFG Project uulm
EU Project THU
Other projects THU
License
CC BY 4.0 International
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Part of
DOI external
DOI external
10.1038/s41698-023-00457-x
Institutions
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DFG Project THU
item.page.thu.projectEU
item.page.thu.projectOther
Series
Keywords
Biomarkers, Cancer genomics, Molecular medicine, DDC 610 / Medicine & health