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

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-CNS<sup>2</sup>, an adaptive-sampling-based nanopore sequencing workflow. Here we comprehensively validated and further developed Rapid-CNS<sup>2</sup> 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-CNS<sup>2</sup> 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.

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Publication Details

Journal
Nature Medicine
Published
2025-03-25
DOI
https://doi.org/10.1038/s41591-025-03562-5
Citations
28
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
45.51

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article

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

Natalie Jaeger, Skarphéðinn Halldórsson, Henning Leske, Dan C. Martin et al.
28 citations
Nature Medicine
Glioma Diagnosis and Treatment
45.51
article

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

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

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-CNS<sup>2</sup>, an adaptive-sampling-based nanopore sequencing workflow. Here we comprehensively validated and further developed Rapid-CNS<sup>2</sup> 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-CNS<sup>2</sup> 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.

Nature MedicineVol. 31(5)
Goethe University Frankfurt (DE), Oslo University Hospital (NO), Cincinnati Children's Hospital Medical Center (US), Nottingham University Hospitals NHS Trust (GB), University College London Hospitals NHS Foundation Trust (GB), University of Nottingham (GB), University of Augsburg (DE), German Cancer Research Center (DE), University of Oslo (NO), Heidelberg University (DE), Ghent University Hospital (BE), University Hospital Heidelberg (DE), University Hospital of Basel (CH), Humboldt-Universität zu Berlin (DE), National Center for Tumor Diseases (DE), Brain (Germany) (DE), Hopp Children's Cancer Center Heidelberg (DE), University Hospital Frankfurt (DE), AZ Delta (BE), Target (Germany) (DE), National Hospital for Neurology and Neurosurgery (GB), Frankfurt Cancer Institute (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), University College London (GB), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE)
Deutsche Forschungsgemeinschaft
Openalex Percentile: Top 0%
Glioma Diagnosis and Treatment
45.51
DOIOpen Access PDFOpenAlex
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