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

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

Published in

Acta neuropathologica communications. Volume 14. Issue 1. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

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.
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.
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.
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.

PMID:
42665813
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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