Low FoxG1 and high Olig-2 labelling indices define a prognostically favorable subset in IDH-mutant gliomas.

Aims: Previous data suggest that expression of transcription factors FoxG1 and Olig-2 can separate hotspot histone H3 family member 3A (H3F3A)-mutant tumours in paediatric glioma. We evaluated their prognostic potential and feasibility for identifying H3F3-Amutant tumours among IDH-mutant/wild-type gliomas. Methods: Immunohistochemistry of FoxG1/Olig-2 and a-thalassaemia/mental-retardation-syndrome-X-linked gene (ATRX) in 471 cases of diffuse gliomas and molecular determination of IDH, H3F3A, MGMT and 1p/19 codeletion status. Results: Mean percentage of FoxG1-positive tumour cells increased from 17% in WHO grade II to over 21% in grade III to 37% in grade IV tumours, whereas mean Olig-2 indices decreased from 29% to 28% to 17% respectively. FoxG1 indices were similar in astrocytic and oligoden-droglial tumours, whereas Olig-2 indices were increased in oligodendrogliomas compared to astrocytic tumours (n = 451, P < 0.0001). FoxG1-positive nuclei were significantly reduced in IDH and H3F3A K27-mutant tumours, whereas Olig-2-positive nuclei were significantly reduced in IDH-wild-type and H3F3A G34-mutant tumours. Among IDH-mutant tumours, mean Olig-2 index was significantly higher in 1p/19q codeleted tumours (mean: 43%) compared to IDH-mutant tumours with ATRX loss (mean: 23%, P < 0.0001). A significantly better outcome was first suggested for FoxG1 low tumours (n = 212, log rank P = 0.0132) and Olig-2 high tumours (n = 203, log-rank P = 0.0011) based on classification and regression tree determined cutoffs, but this was not confirmed by multivariate analysis including IDH mutation, WHO grade, ATRX status and age. Conclusions: While the combined FoxG1/Olig-2 profile may discriminate H3F3A K27-and G34-mutant tumours and define a prognostically favourable subset in IDH-mutant gliomas, our data show that labelling indices of these transcription factors overlap with adult IDH-mutant and wild-type tumour classes.