PSEN1 Expression Identifies a Developmentally Distinct Favourable‐Prognosis State in SHH α Medulloblastoma

ABSTRACT Background Although PSEN1 is best known for its role in Alzheimer's disease, it also regulates neural development and cerebellar morphogenesis. Medulloblastoma (MB) is the most common malignant paediatric brain tumour and arises from disrupted cerebellar developmental programmes. The clinical significance of PSEN1 in MB remains unknown. We investigated the prognostic value and transcriptional correlates of PSEN1 expression across molecular subgroups and subtypes of MB. Methods Public bulk and single‐cell transcriptomic datasets were used to examine PSEN1 expression, associations with overall survival (OS) and transcriptional correlates in MB. The SHH α‐associated transcriptional pattern was evaluated in an independent cohort, and PSEN1 expression was further examined in the developing human cerebellum and across paediatric brain tumour types. Genes strongly correlated with PSEN1 in SHH α MB were subjected to gene ontology (GO) enrichment analysis. Results High PSEN1 expression was consistently associated with significantly longer OS exclusively in SHH α MB. The PSEN1 ‐associated transcriptional pattern was reproduced in an independent SHH α cohort. PSEN1 was expressed across developing cerebellar cell populations and paediatric brain tumour types, with MB showing intermediate expression among the tumour entities examined. In SHH α MB, PSEN1 was associated with a coordinated transcriptional programme enriched for RNA homeostasis, intracellular membrane trafficking, protein quality control, lipid and calcium signalling and developmental pathways. Conclusions High PSEN1 expression identifies a favourable‐prognosis subset of SHH α MB and is associated with a distinct transcriptional programme related to endomembrane organization and cellular homeostasis rather than canonical SHH signalling. These findings suggest that PSEN1 may mark a developmentally distinct tumour state and generate new hypotheses regarding subtype‐specific developmental programmes in MB.