Subgroup-Specific Associations of GRIA Genes Encoding AMPA Glutamate Receptor Subunits with Patient Survival in Medulloblastoma

Abstract Brain cancers hijack biological systems involved in neural development and synaptic plasticity. Medulloblastoma (MB), the most common malignant brain tumor in children, is thought to arise from disruptions in neurodevelopmental programs. Glutamatergic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) has been implicated in synaptic communication between adult brain tumors and surrounding neurons; however, the possible role of AMPARs in MB remains largely unexplored. Here, we analyzed the expression of genes encoding AMPAR subunits, GRIA1–4, in datasets of MB tumors, revealing distinct expression patterns and subgroup-specific associations with overall survival (OS) across molecular subgroups and histological variants. Expression of GRIA1, GRIA3, and GRIA4 was significantly lower in MB in comparison with normal cerebellar tissue. Higher GRIA1, GRIA2, and GRIA4 transcription was associated with more favorable patient outcomes in specific MB subgroups. In contrast, high expression of GRIA3 in SHH, or of either GRIA3 or GRIA4 in Group 3 MB, was associated with worse prognosis. Particularly robust but opposing associations with patient survival were found for GRIA3 and GRIA4 in SHH MB. Analysis of GRIA mRNA levels in MB cell lines representing different molecular subgroups, using data from The Human Protein Atlas, showed partial concordance with expression patterns observed in tumors. Together, these findings suggest that GRIA genes and their corresponding AMPAR subunits may have subgroup-specific prognostic relevance in MB and merit further investigation. Competing Interest Statement The authors have declared no competing interest. Footnotes https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE202043 https://www.proteinatlas.org/ENSG00000155511-GRIA1/cell+line#brain_cancer https://www.proteinatlas.org/ENSG00000120251-GRIA2/cell+line#brain_cancer https://www.proteinatlas.org/ENSG00000125675-GRIA3/cell+line#brain_cancer https://www.proteinatlas.org/ENSG00000152578-GRIA4/cell+line#brain_cancer https://www.proteinatlas.org/ENSG00000155511-GRIA1/cell+line#non-cancerous https://www.proteinatlas.org/ENSG00000120251-GRIA2/cell+line#non-cancerous https://www.proteinatlas.org/ENSG00000125675-GRIA3/cell+line#non-cancerous https://www.proteinatlas.org/ENSG00000152578-GRIA4/cell+line#non-cancerous Abbreviations - AMPA - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid - AMPAR - AMPA receptor - GBM - Glioblastoma - GCP - Granule cell precursor - GEO - Gene Expression Omnibus - GNP - Granule neuron precursor - LCA - Large cell/anaplastic - MB - Medulloblastoma - MBEN - Medulloblastoma with extensive nodularity - mRNA - Messenger ribonucleic acid - NS - Non-significant - OS - Overall survival - qRT-PCR - Quantitative reverse transcription polymerase chain reaction - RL - Rhombic lip - SHH - Sonic hedgehog - Sig - Significant difference - WNT - Wingless