Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci.

Journal

European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235

Informations de publication

Date de publication:
21 Jun 2024
Historique:
received: 21 12 2023
accepted: 10 06 2024
revised: 17 05 2024
medline: 22 6 2024
pubmed: 22 6 2024
entrez: 21 6 2024
Statut: aheadofprint

Résumé

Considering polygenic risk scores (PRSs) in individual risk prediction is increasingly implemented in genetic testing for hereditary breast cancer (BC) based on next-generation sequencing (NGS). To calculate individual BC risks, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) with the inclusion of the BCAC 313 or the BRIDGES 306 BC PRS is commonly used. The PRS calculation depends on accurately reproducing the variant allele frequencies (AFs) and, consequently, the distribution of PRS values anticipated by the algorithm. Here, the 324 loci of the BCAC 313 and the BRIDGES 306 BC PRS were examined in population-specific database gnomAD and in real-world data sets of five centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), to determine whether these expected AFs can be reproduced by NGS-based genotyping. Four PRS loci were non-existent in gnomAD v3.1.2 non-Finnish Europeans, further 24 loci showed noticeably deviating AFs. In real-world data, between 11 and 23 loci were reported with noticeably deviating AFs, and were shown to have effects on final risk prediction. Deviations depended on the sequencing approach, variant caller and calling mode (forced versus unforced) employed. Therefore, this study demonstrates the necessity to apply quality assurance not only in terms of sequencing coverage but also observed AFs in a sufficiently large cohort, when implementing PRSs in a routine diagnostic setting. Furthermore, future PRS design should be guided by the technical reproducibility of expected AFs across commonly used genotyping methods, especially NGS, in addition to the observed effect sizes.

Identifiants

DOI: 10.1038/s41431-024-01647-2 PMID: 38907004
pubmed: 38907004
doi: 10.1038/s41431-024-01647-2
pii: 10.1038/s41431-024-01647-2
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Bundesministerium für Gesundheit (Federal Ministry of Health, Germany)
ID : genomDE
Organisme : Bundesministerium für Gesundheit (Federal Ministry of Health, Germany)
ID : genomDE
Organisme : Deutsche Krebshilfe (German Cancer Aid)
ID : HerediVar

Investigateurs

Stephan Drukewitz (S)
Christoph Engel (C)
Peter Frommolt (P)
Eva Groß (E)
Johannes Helmuth (J)
Zarah Kowalzyk (Z)
Maximilian Radtke (M)
Juliane Ramser (J)
Steffen Uebe (S)
Shan Wang-Gohrke (S)

Informations de copyright

© 2024. The Author(s).

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Auteurs

Alexandra Baumann (A)

Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany.
ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
German Cancer Consortium (DKTK), Dresden, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Christian Ruckert (C)

Department of Medical Genetics, University Hospital Münster, Münster, Germany.

Christoph Meier (C)

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Tim Hutschenreiter (T)

Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany.
ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
German Cancer Consortium (DKTK), Dresden, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Robert Remy (R)

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.

Benedikt Schnur (B)

Department of Human Genetics, Hannover Medical School (MHH), Hannover, Germany.
ORCID: 0000-0002-1977-7878

Marvin Döbel (M)

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.
ORCID: 0000-0002-8024-2178

Rudel Christian Nkouamedjo Fankep (RCN)

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.

Dariush Skowronek (D)

Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.

Oliver Kutz (O)

Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany.
ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
German Cancer Consortium (DKTK), Dresden, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany.

Norbert Arnold (N)

Department of Gynecology and Obstetrics, Institute of Clinical Chemistry Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Anna-Lena Katzke (AL)

Department of Human Genetics, Hannover Medical School (MHH), Hannover, Germany.

Michael Forster (M)

Department of Gynecology and Obstetrics, Institute of Clinical Chemistry Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
ORCID: 0000-0001-9927-5124

Anna-Lena Kobiela (AL)

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.
ORCID: 0009-0000-6391-1280

Katharina Thiedig (K)

Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, München, Germany.

Andreas Zimmer (A)

Institute for Human Genetics, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-5595-9388

Julia Ritter (J)

Department of Human Genetics, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany.

Bernhard H F Weber (BHF)

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.
ORCID: 0000-0002-8808-7723

Ellen Honisch (E)

Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Karl Hackmann (K)

Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology, Dresden, Germany.
ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
German Cancer Consortium (DKTK), Dresden, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
ORCID: 0000-0003-4181-2120

Gunnar Schmidt (G)

Department of Human Genetics, Hannover Medical School (MHH), Hannover, Germany.

Marc Sturm (M)

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.
ORCID: 0000-0002-6552-8362

Corinna Ernst (C)

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany. corinna.ernst@uk-koeln.de.
ORCID: 0000-0001-7756-8815

Classifications MeSH