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

Research output: Contribution to journalResearch articleContributed

Contributors

  • University Hospital Münster
  • University of Regensburg
  • University of Cologne
  • Hannover Medical School (MHH)
  • University of Tübingen
  • Greifswald University Hospital
  • University Hospital Schleswig-Holstein Campus Kiel
  • Technical University of Munich
  • University of Freiburg
  • Labor Berlin Charité-Vivantes GmbH
  • University Hospital Regensburg
  • University Hospital Duesseldorf

Abstract

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.

Details

Original languageEnglish
Pages (from-to)987-997
Number of pages11
JournalEuropean journal of human genetics : EJHG
Volume32
Issue number8
Publication statusPublished - Aug 2024
Peer-reviewedNo

External IDs

PubMedCentral PMC11291653
Scopus 85200423211

Keywords

Sustainable Development Goals

Keywords

  • Humans, Female, Breast Neoplasms/genetics, Multifactorial Inheritance, High-Throughput Nucleotide Sequencing/methods, Genotyping Techniques/methods, Genetic Predisposition to Disease, Genetic Testing/methods, Gene Frequency, Algorithms, Genetic Risk Score