PSEN1 Expression Identifies a Developmentally Distinct Favorable-Prognosis State in SHH α Medulloblastoma

PSEN1, traditionally linked to Alzheimer's disease, also plays a role in neural development and cerebellar growth. Medulloblastoma (MB), the most common pediatric brain cancer, emerges from aberrant cerebellar development patterns. The importance of PSEN1 in MB's prognosis remains unclear. Researchers examined PSEN1 expression, survival outcomes, and transcriptional patterns across various MB subgroups using public datasets.

The SHH-related gene expression profile was assessed in a separate group, and PSEN1 expression was studied in developing human cerebellum and other pediatric brain tumors. Genes highly correlated with PSEN1 in SHH MB underwent Gene Ontology (GO) analysis.

High PSEN1 levels were consistently linked to notably longer survival exclusively in SHH MB. The related gene expression pattern was confirmed in another SHH cohort. PSEN1 was present in the developing cerebellar cells and various pediatric brain cancer types, exhibiting intermediate expression in MB compared to other tumors. In SHH MB, PSEN1 correlated with an intricate transcriptional program involving RNA regulation, cellular membrane transport, protein quality assurance, lipid balance, and calcium homeostasis, as well as developmental processes.

These findings indicate that elevated PSEN1 expression singles out a favorable-prognosis subset of SHH MB and is linked to a unique transcriptional signature tied to endomembrane organization and cellular equilibrium, rather than traditional SHH signaling pathways. This discovery suggests PSEN1 could mark a developmentally distinct state in MB and offer fresh insights into subtype-specific developmental mechanisms in these tumors.