Joint analysis of germline genetic data from over 29,000 cases with suspected hereditary breast and ovarian cancer (HBOC) as part of the NASGE initiative

Joint analysis of germline genetic data from over 29,000 cases with suspected hereditary breast and ovarian cancer (HBOC) as part of the NASGE initiative

As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing...

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Main Authors: Jan Henkel, Andreas Laner, Melanie Locher, Tobias Wohlfrom, Birgit Neitzel, Kerstin Becker, Teresa Neuhann, Angela Abicht, Verena Steinke-Lange, Barbara Klink, Birgit Eichhorn, Winfried Schmidt, Daniel Berner, Anna Teubert, Anne Holtorf, Sarah Heinrich, Gabriele Wildhardt, Martin Schulze, Laura von der Heyden, Konstanze Hörtnagel, Daniela Steinberger, Saskia Kleier, Peter Lorenz, Ralf Glaubitz, Saskia Biskup, Elke Holinski-Feder
Format: Article
Language:English
Published: Elsevier 2025-04-01
Series:Breast
Subjects:
Genetic testing
Hereditary breast and ovarian cancer syndrome
Gene panel testing
Genetic predisposition to disease
Neoplastic syndromes
Hereditary
Online Access:http://www.sciencedirect.com/science/article/pii/S0960977625000165
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Summary:As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing laboratories vary, resulting in a different variant diagnostic rate. Therefore, we performed a retrospective NGS dataset analysis of suspected HBOC patients who had been tested at different German diagnostic laboratories that are part of the NASGE network.We collected 29,317 HBOC datasets and compared the diagnostic yield applying the most common panel recommendations and an internal HBOC gene panel. Additionally, we analyzed the data concerning other potential tumor risk syndromes (TRS) not caused by pathogenic variants in the core panel genes.At least one pathogenic variant causative for an autosomal-dominant TRS was identified in 4235 datasets, resulting in an overall diagnostic yield of 14.4 %. The diagnostic yield of pathogenic variants varied depending on the applied HBOC panel (between 5 and 26 genes) from 9.0 % to 13.8 % with the internal HBOC panel having a yield of 12.7 %. Notably, in about 1 % of cases, a pathogenic variant outside the established HBOC core genes was identified, indicating the presence of other TRS.These results are consistent with previous observations that a significant proportion of patients with HBOC predisposition were not detected by the guideline-based gene panels and suggest that expanded diagnostics compared to currently recommended multigene panels may identify additional patients at high risk for developing cancer.
ISSN:1532-3080

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