A proteome-based classification of pediatric adrenocortical tumors links functional tumor states to clinical outcome and therapeutic vulnerabilities
Claus, R.; Metousis, A.; Fincke, V.; Kunstreich, M.; Wudy, S. A.; Juettner, E.; Pons-Kuehnemann, J.; Vokuhl, C.; Fruehwald, M. C.; Roecken, C.; Schweizer, L.; Johann, P. D.; Redlich, A.; Mann, M.; Kuhlen, M.
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Pediatric adrenocortical tumors (pACT) are biologically heterogeneous and incompletely clas-sified by histopathology. To elucidate proteome-level tumor organization, we performed mass spectrometry-based proteomic profiling of 83 pACT and 43 normal adrenal samples. Unsu-pervised clustering identified four distinct molecular subtypes partially overlapping with histo-logical diagnoses. These subtypes reflected discrete biological states: stromal-immune enrichment with reduced steroidogenesis, mitochondrial and steroidogenic activation, IGF/mTOR-driven anabolic reprogramming, and highly proliferative chromatin-remodeled carcinoma states. Proteomic clusters correlated strongly with endocrine phenotype, proliferative index, vascular invasion, and survival, outperforming conventional pathology. A five-protein classifier (DAAM2, CIP2A, TSC2, PALS2, P3H1) reproduced subtype structure with 92.8% cross-validated accuracy. Cluster-specific analysis therapeutic vulnerabilities, including IGF-axis activation and epigenetic and DNA replication targets in aggressive tumors. These data establish a proteome-based classification of pACT integrating metabolic, proliferative, immune features, providing a framework for molecularly guided risk assessment and precision therapy in this rare cancer.
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