Exceptionally rare IDH1-mutant adult medulloblastoma with concurrent GNAS mutation revealed by in vivo magnetic resonance spectroscopy and deep sequencing

Acta Neuropathol Commun. 2023 Mar 20;11(1):47. doi: 10.1186/s40478-023-01531-y.


Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adults. Based on transcriptome profile, MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) mutations have been described in several tumors, including gliomas, while in MB are rarely reported and not routinely investigated. By means of magnetic resonance spectroscopy (MRS), we unequivocally assessed the presence the oncometabolite D-2-hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutations, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also rarely described in MB. To the best of our knowledge, this is the first reported case of MB simultaneously harboring both mutations. Of note, tumor exhibited a heterogeneous phenotype with a tumor component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting co-existence of two different major tumor subclones. These findings drew attention to the need for a deeper genetic characterization of MB, in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, our results underlined the importance of performing MRS for the identification of IDH mutations in non-glial tumors. The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.

Keywords: GNAS mutation; Isocitrate dehydrogenase 1 and 2 mutation; Magnetic resonance spectroscopy (MRS); Medulloblastoma; d-2-Hydroxyglutarate (2HG).

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms* / genetics
  • Cerebellar Neoplasms* / diagnostic imaging
  • Cerebellar Neoplasms* / genetics
  • Chromogranins / genetics
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Glioma* / genetics
  • Glutarates / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Magnetic Resonance Spectroscopy / methods
  • Medulloblastoma* / diagnostic imaging
  • Medulloblastoma* / genetics
  • Mutation / genetics


  • Isocitrate Dehydrogenase
  • Glutarates
  • GNAS protein, human
  • Chromogranins
  • GTP-Binding Protein alpha Subunits, Gs
  • IDH1 protein, human