M-PACT leverages cell-free DNA methylomes to achieve robust classification of pediatric brain tumors
Cerebrospinal fluid (CSF) liquid biopsies serve as a rich source of tumor-derived cell-free DNA (cfDNA) for evaluating persons with central nervous system (CNS) tumors. However, challenges stemming from trace cfDNA yields and low mutational burden have hindered sensitivity, whereas first-generation clinical assays have relied on genetic alterations as biomarkers. Leveraging the diagnostic utility of DNA methylation classification in CNS tumors, we developed M-PACT (methylation-based predictive algorithm for CNS tumors), a robust deep neural network that accurately classifies tumors from subnanogram-input cfDNA methylomes. Across embryonal CNS tumor benchmarking (n = 79) and validation (n = 58) cohorts, M-PACT achieved 92% and 88% accuracy, respectively. We further showcase M-PACT utility in nonembryonal CNS tumors, balanced tumor genomes and nonmalignant CSF. Beyond classification, this workflow enables methylation-based cellular deconvolution and sensitive copy-number variation detection. Altogether, we provide a blueprint for CNS tumor classification from low-input cfDNA methylomes, motivating prospective validation for future clinical implementation.
Authors
- Kristiina Nordfors (ORCID: https://orcid.org/0000-0002-3680-4524)
- Martin G. McCabe (ORCID: https://orcid.org/0000-0002-5138-0707)
- Taha Soliman (ORCID: https://orcid.org/0000-0003-3185-3092)
- Sibylle Madlener (ORCID: https://orcid.org/0000-0001-7099-9997)
- Brent A. Orr (ORCID: https://orcid.org/0000-0003-0997-4728)
- Patrick R. Blackburn (ORCID: https://orcid.org/0000-0003-0658-1275)
- Johannes Gojo (ORCID: https://orcid.org/0000-0002-8113-3416)
- Natalia Stepien (ORCID: https://orcid.org/0000-0002-6658-8367)
- Tom T. Fischer (ORCID: https://orcid.org/0000-0002-2138-9102)
- H. Haapasalo
- Giles W Robinson (ORCID: https://orcid.org/0000-0001-7441-9486)
- Paul Northcott
- Daniel Senfter (ORCID: https://orcid.org/0000-0001-9203-4563)
- Justina Dargvainiene (ORCID: https://orcid.org/0009-0002-4114-3748)
- Nathalie Schwarz
- Judith M. de Bont
- Kendra K. Maaß (ORCID: https://orcid.org/0000-0001-9357-5038)
- Anna Kostecka
- Stefanie Volz
- Maria T. Schmook
- Frank Leypoldt
- Sandeep K Dhanda
- Stefan M. Pfister
- Amar Gajjar
- Hong Lin
- Katie Han
- Esther Hulleman
- Kyle S. Smith
- Christine Haberler
- Joonas Haapasalo
Institutions
- St. Jude Children's Research Hospital (US)
- Tampere University (FI)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Comprehensive Cancer Center Vienna (AT)
- National Center for Tumor Diseases (DE)
- University Hospital Schleswig-Holstein (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Tampere University Hospital (FI)
- Princess Máxima Center (NL)
- Tampere University (FI)
- Fimlab (Finland) (FI)
- Amsterdam University Medical Centers (NL)
- Medical University of Vienna (AT)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2026-02-17
- DOI
- https://doi.org/10.1038/s43018-026-01115-4
- Citations
- 1
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 36.93