Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation

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.

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Journal
Acta Neuropathologica Communications
Published
2026-08-28
DOI
https://doi.org/10.1186/s40478-026-02411-x
Primary Topic
Glioma Diagnosis and Treatment
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article
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article

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation

Christoph Kleinschnitz, Raphael Bodensohn, Clemens Seidel, Christina Schaub et al.
Acta Neuropathologica Communications
Glioma Diagnosis and Treatment
article

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation

Christoph Kleinschnitz, Raphael Bodensohn, Clemens Seidel, Christina Schaub, Michael C. Burger, Volker Neuschmelting, Tobias Blau, Sied Kebir, Felix Behling, David Capper, Jens Schittenhelm, Benjamin Thiele, Davide Tosin, Kathy Keyvani, Ulrich Sure, Jörg Felsberg, Beate Timmermann, Dorothea Miller, Malte Mohme, Michael Müther, Michael Platten, Xiaomei Zhou, Stephan Frank, Martin Stuschke, Maximilian Scheer, Teresa Schmidt, Christoph Oster, Niklas Thon, Elke Pfaff, Stephan Tippelt, Laurèl Rauschenbach, Georg Karpel‐Massler, Sarina Agkatsev, Sabine Seidel, Ghazaleh Tabatabai, Jürgen Hench, Joachim P. Steinbach, Naomi Houedjissin, Julia Onken, Corinna Seliger, André Sagerer, Viktoria Ruf, Lazaros Lazaridis, Christian Thomas, Andrea Tannapfel, Ilinca Popp, Guido Reifenberger, Marcos Tatagiba, Martin Hasselblatt, Regina von Manitius
article en

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.

Acta Neuropathologica CommunicationsVol. 14(1)
Goethe University Frankfurt (DE), Goethe-Institute United Kingdom (GB), Universität Hamburg (DE), University of Augsburg (DE), German Cancer Research Center (DE), University of Cologne (DE), Universität Ulm (DE), Heidelberg University (DE), University Hospital Bonn (DE), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), University Hospital of Basel (CH), LMU Klinikum (DE), Düsseldorf University Hospital (DE), Integrated Oncology (United States) (US), German Cancer Society (DE), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), Universitätsklinikum Knappschaftskrankenhaus Bochum (DE), Essen University Hospital (DE), University Children's Hospital Tübingen (DE), University Hospital Leipzig (DE), Hertie Institute for Clinical Brain Research (DE), University Hospital Cologne (DE), West German Heart and Vascular Center Essen (DE), University Hospital Carl Gustav Carus (DE), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Ruhr University Bochum (DE)
Universitätsklinikum Essen
Good health and well-being
Openalex Percentile: Top 11%
Glioma Diagnosis and Treatment
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