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

Volume Title

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

Citation

DFG Project uulm

EU Project THU

Other projects THU

License

CC BY 4.0 International

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Supplement to

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Erratum to

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Part of

DOI external

DOI external

10.1038/s41698-023-00457-x

Institutions

Periodical

Degree Program

DFG Project THU

item.page.thu.projectEU

item.page.thu.projectOther

Series

Keywords

Biomarkers, Cancer genomics, Molecular medicine, DDC 610 / Medicine & health