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