Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. METHODS: We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. RESULTS: Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association. CONCLUSIONS: Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.
Authors: Lazaros Lazaridis, Xiaomei Zhou, Raphael Bodensohn, Malte Mohme, Julia Onken, Regina von Manitius, Naomi Houedjissin, Tobias Blau, Ilinca Popp, Sarina Agkatsev, Sabine Seidel, Christina Schaub, Maximilian Scheer, Andre Sagerer, Volker Neuschmelting, Davide Tosin, Viktoria Ruf, Michael C. Burger, Christoph Oster, Teresa Schmidt, Benjamin Thiele, Jürgen Hench, Stephan Frank, Martin Stuschke, Laurèl Rauschenbach, Stephan Tippelt, Beate Timmermann, Kathy Keyvani, Clemens Seidel, Andrea Tannapfel, Dorothea Miller, Niklas Thon, Joachim P. Steinbach, Elke Pfaff, Georg Karpel-Massler, Jörg Felsberg, Guido Reifenberger, Marcos Tatagiba, Ghazaleh Tabatabai, Jens Schittenhelm, Christian Thomas, Martin Hasselblatt, Corinna Seliger, Christoph Kleinschnitz, Ulrich Sure, David Capper, Michael Platten, Felix Behling, Michael Müther, Sied Kebir
Institutions: Universitätsklinikum Knappschaftskrankenhaus Bochum, Ruhr University Bochum, University of Duisburg-Essen, Universitätsklinikum Tübingen, University of Tübingen, University Medical Center Hamburg-Eppendorf, Charité - Universitätsmedizin Berlin, Stiftung Charité, Heinrich Heine University Düsseldorf, Stiftung Universitätsmedizin Essen, University of Freiburg, University Medical Center Freiburg, University of Bonn, University Hospital Bonn, University Hospital Heidelberg, Technische Universität Dresden, University of Cologne, University Hospital Cologne, Universität Ulm, University Hospital Ulm, Institut für Neuropathologie, Ludwig-Maximilians-Universität München, Goethe University Frankfurt, University Hospital Frankfurt, German Cancer Research Center, Essen University Hospital, Deutsches Konsortium für Translationale Krebsforschung, University of Basel, University Hospital of Basel, University Hospital Leipzig, Heidelberg University, Düsseldorf University Hospital, Hertie Institute for Clinical Brain Research, University Hospital Münster, Medizinische Fakultät Mannheim, University of Augsburg
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Funder: Universitätsklinikum Essen
OpenAlex ID: W7204568359