gms | German Medical Science

Objective: Gangliogliomas (GGs) are the most common entity in the glioneuronal neoplasm spectrum. Recently frequent BRAFV600E mutations and increased mTOR pathway signaling were observed in GGs, and alterations in p53 have been related to its rare malignant progression. However, the histogenesis of this tumor entity has so far remained unresolved and here we aim to analyze the ontogeny of this tumor entity by using new mouse models which develop distinct GG-like neoplasms dependent on the combination of genetic modifications.

Methods: We performed intraventricular in utero electroporation (IUE) of vectors encoding BRAFV600E, constitutively active Akt kinase (pAkt) or Cre under the control of different promoters in distinct combinations in p53flox/flox mice at embryonic day 14 (E14). The cyto- and histological features, immunohistochemical and molecular profiles of emerging tumors in adult mice and their survival kinetics were analyzed.

Results: IUE of CAG-BRAFV600E alone and co-IUE of CAG-BRAFV600E and –pAkt induced very benign GG-like tumors. Occasionally GGs showed malignant progression and these tumors were associated with mutations of the tumor suppressor p53 mainly in the glial component. We addressed this aspect by co-IUE of SynI-BRAFV600E with glial fibrillary acid promoter (GFAP)-Cre in p53flox/flox mice. Ablation of p53 in only the glial component worsens the biological behavior of tumors and induces a very prominent dysplastic, often bi-nucleated neuronal phenotype. We observed the shortest overall-survival in mice with GG-like neoplasm induced by co-IUE of CAG-BRAFV600E, -pAkt and –Cre in p53flox/flox mice. Furthermore, by mRNA sequencing and comparative transcriptomic analysis we elucidated the differentially expressed transcripts in individual tumor entities.

Conclusion: The particular distribution of genetic alterations has fundamental impact on neuropathological appearance and key biological features of the emerging neoplasms. These aspects need consideration for the stratification of human GGs particularly with respect to tailor-made therapies targeting distinct molecular cascades.