Prospective, multicenter validation of a platform for rapid molecular profiling of central nervous system tumors

Patel, Areeba; Göbel, Kirsten; Ille, Sebastian; Hinz, Felix; Schoebe, Natalie; Bogumil, Henri; Meyer, Jochen; Brehm, Michelle; Kardo, Helin; Schrimpf, Daniel; Lomakin, Artem; Ritter, Michael; Göller, Pauline; Kerbs, Paul; Pfeifer, Lisa; Hamelmann, Stefan; Blume, Christina; Ippen, Franziska M.; Berghaus, Natalie; Euskirchen, Philipp; Schweizer, Leonille; Hultschig, Claus; Van Roy, Nadine; Van Dorpe, Jo; Van der Meulen, Joni; Loontiens, Siebe; Dedeurwaerdere, Franceska; Leske, Henning; Halldórsson, Skarphéðinn; Fox, Graeme; Deacon, Simon; Cahyani, Inswasti; Holmes, Nadine; Wibowo, Satrio; Munro, Rory; Martin, Dan; Sharif, Abid; Housley, Mark; Goldspring, Robert; Brandner, Sebastian; Roy, Somak; Hench, Jürgen; Frank, Stephan; Unterberg, Andreas; Goidts, Violaine; Jäger, Natalie; Paine, Simon; Smith, Stuart; Herold-Mende, Christel; Wick, Wolfgang; Pfister, Stefan M.; Vik-Mo, Einar O.; von Deimling, Andreas; Krieg, Sandro; Jones, David TW; Loose, Matthew; Schlesner, Matthias; Sill, Martin;...

Abstract

Molecular data integration plays a central role in central nervous system (CNS) tumor diagnostics but currently used assays pose limitations due to technical complexity, equipment and reagent costs, as well as lengthy turnaround times. We previously reported the development of Rapid-CNS2, an adaptive-sampling-based nanopore sequencing workflow. Here we comprehensively validated and further developed Rapid-CNS2 for intraoperative use. It now offers real-time methylation classification and DNA copy number information within a 30-min intraoperative window, followed by comprehensive molecular profiling within 24 h, covering the complete spectrum of diagnostically and therapeutically relevant information for the respective entity. We validated Rapid-CNS2 in a multicenter setting on 301 archival and prospective samples including 18 samples sequenced intraoperatively. To broaden the utility of methylation-based CNS tumor classification, we developed MNP-Flex, a platform-agnostic methylation classifier encompassing 184 classes. MNP-Flex achieved 99.6% accuracy for methylation families and 99.2% accuracy for methylation classes with clinically applicable thresholds across a global validation cohort of more than 78,000 frozen and formalin-fixed paraffin-embedded samples spanning five different technologies. Integration of these tools has the potential to advance CNS tumor diagnostics by providing broad access to rapid, actionable molecular insights crucial for personalized treatment strategies.

Citation

Patel, A., Göbel, K., Ille, S., Hinz, F., Schoebe, N., Bogumil, H., Meyer, J., Brehm, M., Kardo, H., Schrimpf, D., Lomakin, A., Ritter, M., Göller, P., Kerbs, P., Pfeifer, L., Hamelmann, S., Blume, C., Ippen, F. M., Berghaus, N., Euskirchen, P., …Sahm, F. (2025). Prospective, multicenter validation of a platform for rapid molecular profiling of central nervous system tumors. Nature Medicine, https://doi.org/10.1038/s41591-025-03562-5

• Journal Article Type: Article
• Acceptance Date: Feb 4, 2025
• Online Publication Date: Mar 25, 2025
• Publication Date: Mar 25, 2025
• Deposit Date: Apr 1, 2025
• Publicly Available Date: Apr 2, 2025
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s41591-025-03562-5
• Public URL: https://nottingham-repository.worktribe.com/output/47260885
• Publisher URL: https://www.nature.com/articles/s41591-025-03562-5
• Additional Information: Received: 28 March 2024; Accepted: 4 February 2025; First Online: 25 March 2025