CpG hypermethylation and WNT/AP-1 cooperativity define the epigenetic landscape and a clinical subgroup of high-risk pediatric adrenocortical carcinoma
Abstract Pediatric adrenocortical tumors are rare, clinically heterogeneous neoplasms with unpredictable outcomes and limited treatment options. Through integrated multi-omic analysis of 214 pediatric adrenocortical tumors combining DNA methylation profiling, transcriptomics, chromatin accessibility, and spatial deconvolution, we identify four distinct risk groups. A high-risk subgroup is characterized by CpG island hypermethylation, chromosomal instability, and dismal survival. These tumors exhibit transcriptional co-activation of WNT signalling and activator protein-1 transcriptional programs and display balanced admixture of zona glomerulosa and zona fasciculata/reticularis-like cells. Spatial analysis reveals zona glomerulosa cells as WNT signaling hubs driving intercellular crosstalk. Mechanistically, the histone deacetylase inhibitor entinostat reverses promoter methylation, silences activator protein-1 activity, and induces apoptotic reprogramming in tumor models. These findings establish a molecular framework for risk stratification and identify actionable therapeutic vulnerabilities, providing an essential resource for studying this molecularly uncharted pediatric malignancy.
Authors
- Ina Oehme (ORCID: https://orcid.org/0000-0002-0827-2356)
- Antje Redlich (ORCID: https://orcid.org/0000-0002-1732-1869)
- Eva Jüttner
- Bruno Märkl (ORCID: https://orcid.org/0000-0002-7704-850X)
- Heike Peterziel (ORCID: https://orcid.org/0000-0001-9261-7144)
- Enrique Blanco-Carmona (ORCID: https://orcid.org/0000-0002-1208-1691)
- Marlena Mucha (ORCID: https://orcid.org/0000-0001-9009-3383)
- Nic G. Reitsam (ORCID: https://orcid.org/0000-0002-0070-3158)
- Stefan M. Pfister (ORCID: https://orcid.org/0000-0002-5447-5322)
- Michael C. Frühwald (ORCID: https://orcid.org/0000-0002-8237-1854)
- Marina Kunstreich (ORCID: https://orcid.org/0000-0002-2672-4045)
- Sebastian Dintner (ORCID: https://orcid.org/0000-0002-0530-0673)
- Rainer Claus (ORCID: https://orcid.org/0000-0003-2617-8766)
- Pascal D. Johann (ORCID: https://orcid.org/0000-0002-8857-6148)
- Matthias Schlesner (ORCID: https://orcid.org/0000-0002-5896-4086)
- Victoria E. Fincke (ORCID: https://orcid.org/0000-0001-7488-6885)
- Martin Sill (ORCID: https://orcid.org/0000-0001-7616-7665)
- Irmengard Sax
- Maurice Loßner
- Jörg Fuchs (ORCID: https://orcid.org/0000-0001-6145-2391)
- Felix Dorn
- Eva Sipos
- Christoph Slavetinsky
- Konstantin Okonechnikov
- Christian Vokuhl
- Michaela Kuhlen
- Maria D. Hernandez Ramirez
- Stefan Wudy
- Lorenz C. Helmschrott
Institutions
- University of Augsburg (DE)
- German Cancer Research Center (DE)
- Justus-Liebig-Universität Gießen (DE)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- University Hospital Augsburg (DE)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- University Hospital Schleswig-Holstein (DE)
- University Children's Hospital Tübingen (DE)
- University Hospital Magdeburg (DE)
- University Hospital Carl Gustav Carus (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Else Kröner Fresenius Center for Digital Health (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-14
- DOI
- https://doi.org/10.1038/s41467-026-77225-5
- Primary Topic
- Adrenal and Paraganglionic Tumors
- Type
- article
- Field-Weighted Citation Impact
- 0.00