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Medulloblastoma (MB) is the most common malignant paediatric brain tumour and arises from disrupted cerebellar developmental programmes. The clinical significance of\n                      <jats:italic>PSEN1<\/jats:italic>\n                      in MB remains unknown. We investigated the prognostic value and transcriptional correlates of\n                      <jats:italic>PSEN1<\/jats:italic>\n                      expression across molecular subgroups and subtypes of MB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Public bulk and single\u2010cell transcriptomic datasets were used to examine\n                      <jats:italic>PSEN1<\/jats:italic>\n                      expression, associations with overall survival (OS) and transcriptional correlates in MB. The SHH \u03b1\u2010associated transcriptional pattern was evaluated in an independent cohort, and\n                      <jats:italic>PSEN1<\/jats:italic>\n                      expression was further examined in the developing human cerebellum and across paediatric brain tumour types. Genes strongly correlated with\n                      <jats:italic>PSEN1<\/jats:italic>\n                      in SHH \u03b1 MB were subjected to gene ontology (GO) enrichment analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High\n                      <jats:italic>PSEN1<\/jats:italic>\n                      expression was consistently associated with significantly longer OS exclusively in SHH \u03b1 MB. The\n                      <jats:italic>PSEN1<\/jats:italic>\n                      \u2010associated transcriptional pattern was reproduced in an independent SHH \u03b1 cohort.\n                      <jats:italic>PSEN1<\/jats:italic>\n                      was expressed across developing cerebellar cell populations and paediatric brain tumour types, with MB showing intermediate expression among the tumour entities examined. In SHH \u03b1 MB,\n                      <jats:italic>PSEN1<\/jats:italic>\n                      was associated with a coordinated transcriptional programme enriched for RNA homeostasis, intracellular membrane trafficking, protein quality control, lipid and calcium signalling and developmental pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      High\n                      <jats:italic>PSEN1<\/jats:italic>\n                      expression identifies a favourable\u2010prognosis subset of SHH \u03b1 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\n                      <jats:italic>PSEN1<\/jats:italic>\n                      may mark a developmentally distinct tumour state and generate new hypotheses regarding subtype\u2010specific developmental programmes in MB.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jdn.70178","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:37:31Z","timestamp":1789432651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>PSEN1<\/i>\n                    Expression Identifies a Developmentally Distinct Favourable\u2010Prognosis State in SHH \u03b1 Medulloblastoma"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-5460","authenticated-orcid":false,"given":"Julia","family":"Vanini","sequence":"first","affiliation":[{"name":"Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE\u2010HCPA) Federal University of Rio Grande do Sul  Porto Alegre Brazil"},{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Thomaz","sequence":"additional","affiliation":[{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"},{"name":"Department of Biology Edge Hill University  Ormskirk UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9754-4809","authenticated-orcid":false,"given":"Marina M\u00fcller","family":"Lupatini","sequence":"additional","affiliation":[{"name":"Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE\u2010HCPA) Federal University of Rio Grande do Sul  Porto Alegre Brazil"},{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-1279","authenticated-orcid":false,"given":"Andr\u00e9 T.","family":"Brunetto","sequence":"additional","affiliation":[{"name":"Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE\u2010HCPA) Federal University of Rio Grande do Sul  Porto Alegre Brazil"},{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"},{"name":"Children's Cancer Institute (ICI)  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-6626","authenticated-orcid":false,"given":"Caroline Brunetto","family":"de Farias","sequence":"additional","affiliation":[{"name":"Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE\u2010HCPA) Federal University of Rio Grande do Sul  Porto Alegre Brazil"},{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"},{"name":"Children's Cancer Institute (ICI)  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3465-4083","authenticated-orcid":false,"given":"Mariane","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE\u2010HCPA) Federal University of Rio Grande do Sul  Porto Alegre Brazil"},{"name":"National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology\u2014INCT BioOncoPed  Porto Alegre Brazil"},{"name":"Children's Cancer Institute (ICI)  Porto Alegre 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