Baumann, Alexandra and Ruckert, Christian and Meier, Christoph and Hutschenreiter, Tim and Remy, Robert and Schnur, Benedikt and Doebel, Marvin and Fankep, Rudel Christian Nkouamedjo and Skowronek, Dariush and Kutz, Oliver and Arnold, Norbert and Katzke, Anna-Lena and Forster, Michael and Kobiela, Anna-Lena and Thiedig, Katharina and Zimmer, Andreas and Ritter, Julia and Weber, Bernhard H. F. and Honisch, Ellen and Hackmann, Karl and Schmidt, Gunnar and Sturm, Marc and Ernst, Corinna and Arnold, Norbert and Baumann, Alexandra and Dobel, Marvin and Drukewitz, Stephan and Engel, Christoph and Ernst, Corinna and Fankep, Rudel Christian Nkouamedjo and Forster, Michael and Frommolt, Peter and Gross, Eva and Hackmann, Karl and Helmuth, Johannes and Honisch, Ellen and Hutschenreiter, Tim and Katzke, Anna-Lena and Kobiela, Anna-Lena and Kowalzyk, Zarah and Kutz, Oliver and Meier, Christoph and Radtke, Maximilian and Ramser, Juliane and Remy, Robert and Ritter, Julia and Ruckert, Christian and Schmidt, Gunnar and Schnur, Benedikt and Skowronek, Dariush and Sturm, Marc and Thiedig, Katharina and Uebe, Steffen and Wang-Gohrke, Shan and Zimmer, Andreas (2024) Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci. EUROPEAN JOURNAL OF HUMAN GENETICS, 32 (8). pp. 987-997. ISSN 1018-4813, 1476-5438
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Jan 2026 07:25 |
| Last Modified: | 14 Jan 2026 07:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65410 |
Actions (login required)
 |
View Item |
