A proteome-based classification of paediatric adrenocortical tumours links functional tumour states to clinical outcome and therapeutic vulnerabilities.
Abstract
Background
Paediatric adrenocortical tumours (pACT) are rare endocrine neoplasms characterised by marked biological heterogeneity and variable clinical behaviour. Current risk stratification relies largely on histopathology and clinical staging, which incompletely capture underlying tumour biology. We aimed to define proteome-based subtypes of pACT and evaluate their biological, clinical, and therapeutic relevance.Methods
In this retrospective cohort study, we performed mass spectrometry-based proteomic profiling of 83 pACT and adjacent non-tumour adrenal tissues. Differential abundance analysis, pathway enrichment, consensus clustering, survival analyses, and clinicopathological correlations were performed. A minimal protein classifier was derived using forward feature selection and leave-one-out cross-validation. Cluster-specific therapeutic vulnerabilities were assessed using a curated druggability framework.Findings
Tumours displayed profound proteomic differences compared with adjacent non-tumour adrenal cortex, characterised by activation of cholesterol biosynthesis, steroidogenic, MYC, mTORC1, and cell-cycle programs and suppression of extracellular matrix, adhesion, and immune-related pathways. Unsupervised clustering identified four proteome-defined tumour states that only partially overlapped with histopathological diagnosis. These subtypes differed significantly in endocrine phenotype, vascular invasion, Ki67 index, necrosis, and overall survival (log-rank p = 0.00036). Distinct biological programs included stromal-immune-enriched, mitochondrial steroidogenic, IGF/mTOR-driven anabolic, and highly proliferative chromatin-remodelled states. A five-protein classifier (DAAM2, CIP2A, TSC2, PALS2, and P3H1) reproduced cluster assignments with 92.8% leave-one-out cross-validation accuracy. Cluster-specific analyses identified distinct therapeutic target landscapes, including IGF-axis and epigenetic vulnerabilities.Interpretation
Proteomic profiling defines biologically and clinically distinct pACT subtypes that provide prognostic information beyond histopathology. This framework enables proteome-based stratification, identifies candidate therapeutic vulnerabilities, and can be approximated by a five-protein classifier.Funding
German Childhood Cancer Foundation, Mitteldeutsche Kinderkrebsforschung, European Union's EU4Health Programme, Max Planck Society, Onassis Foundation, and Joachim Herz Stiftung.
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BibTeX
@article{claus2026proteomebased,
title = {{A proteome-based classification of paediatric adrenocortical tumours links functional tumour states to clinical outcome and therapeutic vulnerabilities.}},
author = {Rainer Claus and Andreas Metousis and Victoria E. Fincke and Marina Kunstreich and Stefan A. Wudy and Eva Jüttner and Joern Pons-Kühnemann and Christian Vokuhl and Michael C. Frühwald and Christoph Röcken and Lisa Schweizer and Pascal D. Johann and Antje Redlich and Matthias Mann and Michaela Kuhlen},
journal = {EBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106504},
url = {https://europepmc.org/article/MED/42843113},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A proteome-based classification of paediatric adrenocortical tumours links functional tumour states to clinical outcome and therapeutic vulnerabilities.
AU - Rainer Claus
AU - Andreas Metousis
AU - Victoria E. Fincke
AU - Marina Kunstreich
AU - Stefan A. Wudy
AU - Eva Jüttner
AU - Joern Pons-Kühnemann
AU - Christian Vokuhl
AU - Michael C. Frühwald
AU - Christoph Röcken
AU - Lisa Schweizer
AU - Pascal D. Johann
AU - Antje Redlich
AU - Matthias Mann
AU - Michaela Kuhlen
PY - 2026
DA - 2026/10/07
JO - EBioMedicine
DO - 10.1016/j.ebiom.2026.106504
UR - https://europepmc.org/article/MED/42843113
AB - Background Paediatric adrenocortical tumours (pACT) are rare endocrine neoplasms characterised by marked biological heterogeneity and variable clinical behaviour. Current risk stratification relies largely on histopathology and clinical staging, which incompletely capture underlying tumour biology. We aimed to define proteome-based subtypes of pACT and evaluate their biological, clinical, and therapeutic relevance.Methods In this retrospective cohort study, we performed mass spectrometry-based proteomic profiling of 83 pACT and adjacent non-tumour adrenal tissues. Differential abundance analysis, pathway enrichment, consensus clustering, survival analyses, and clinicopathological correlations were performed. A minimal protein classifier was derived using forward feature selection and leave-one-out cross-validation. Cluster-specific therapeutic vulnerabilities were assessed using a curated druggability framework.Findings Tumours displayed profound proteomic differences compared with adjacent non-tumour adrenal cortex, characterised by activation of cholesterol biosynthesis, steroidogenic, MYC, mTORC1, and cell-cycle programs and suppression of extracellular matrix, adhesion, and immune-related pathways. Unsupervised clustering identified four proteome-defined tumour states that only partially overlapped with histopathological diagnosis. These subtypes differed significantly in endocrine phenotype, vascular invasion, Ki67 index, necrosis, and overall survival (log-rank p = 0.00036). Distinct biological programs included stromal-immune-enriched, mitochondrial steroidogenic, IGF/mTOR-driven anabolic, and highly proliferative chromatin-remodelled states. A five-protein classifier (DAAM2, CIP2A, TSC2, PALS2, and P3H1) reproduced cluster assignments with 92.8% leave-one-out cross-validation accuracy. Cluster-specific analyses identified distinct therapeutic target landscapes, including IGF-axis and epigenetic vulnerabilities.Interpretation Proteomic profiling defines biologically and clinically distinct pACT subtypes that provide prognostic information beyond histopathology. This framework enables proteome-based stratification, identifies candidate therapeutic vulnerabilities, and can be approximated by a five-protein classifier.Funding German Childhood Cancer Foundation, Mitteldeutsche Kinderkrebsforschung, European Union's EU4Health Programme, Max Planck Society, Onassis Foundation, and Joachim Herz Stiftung.
SN - 2352-3964
ER -