Journal Article

DKFZ-2026-02276

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CpG hypermethylation and WNT/AP-1 cooperativity define the epigenetic landscape and a clinical subgroup of high-risk pediatric adrenocortical carcinoma.

Fincke, V. E. ; Loßner, M. ; Kunstreich, M. ; Reitsam, N. G. ; Sax, I. ; Mucha, M. ; Dorn, F. ; Helmschrott, L. C. ; Hernandez Ramirez, M. D. ; Dintner, S. ; Okonechnikov, K.DKFZ* ; Sill, M.DKFZ* ; Oehme, I.DKFZ* ; Peterziel, H.DKFZ* ; Blanco-Carmona, E. ; Sipos, E. ; Wudy, S. ; Slavetinsky, C. ; Fuchs, J. ; Märkl, B. ; Jüttner, E. ; Vokuhl, C. ; Frühwald, M. C. ; Redlich, A. ; Pfister, S.DKFZ* ; Schlesner, M. ; Claus, R. ; Kuhlen, M. ; Johann, P. D.

2026
Springer Nature [London]

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.

Keyword(s): Humans (MeSH) ; DNA Methylation: genetics (MeSH) ; DNA Methylation: drug effects (MeSH) ; Adrenal Cortex Neoplasms: genetics (MeSH) ; Adrenal Cortex Neoplasms: pathology (MeSH) ; Adrenal Cortex Neoplasms: metabolism (MeSH) ; Adrenal Cortex Neoplasms: mortality (MeSH) ; CpG Islands: genetics (MeSH) ; Epigenesis, Genetic (MeSH) ; Adrenocortical Carcinoma: genetics (MeSH) ; Adrenocortical Carcinoma: pathology (MeSH) ; Adrenocortical Carcinoma: metabolism (MeSH) ; Adrenocortical Carcinoma: mortality (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Child (MeSH) ; Female (MeSH) ; Wnt Signaling Pathway: genetics (MeSH) ; Animals (MeSH) ; Pyridines: pharmacology (MeSH) ; Benzamides: pharmacology (MeSH) ; Male (MeSH) ; Child, Preschool (MeSH) ; Promoter Regions, Genetic (MeSH) ; Cell Line, Tumor (MeSH) ; Wnt Proteins: metabolism (MeSH) ; Wnt Proteins: genetics (MeSH) ; Mice (MeSH) ; Pyridines ; Benzamides ; entinostat ; Wnt Proteins

Note: #DKTKZFB26# / #NCTZFB26#

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

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