Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric‐ and adult‐type gliomas

The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker.

type high-grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10.RTK2 cases were all negative for both OLIG2 and SOX10.MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10.In glioblastoma, IDH-wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype.All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1-altered, and subependymal giant cell astrocytomas.SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2-activated.Conclusion: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult-type HGG.

Keywords: CNS tumours, glioma, OLIG2, SOX10
The SOX10 transcription factor is a protein involved in the regulation of embryonic development and the determination of cell fate.Its expression is known to Address for correspondence: Arnault Tauzi ede-Espariat, Department of Neuropathology, GHU Paris-Neurosciences, Sainte-Anne Hospital.1, rue Cabanis, Paris 75014, France.e-mail: a.tauziedeespariat@ghu-paris.frbe essential for the formation of enteric nerves and the production of melanocytes.It is also important for the maturation of the oligodendrocytes involved in central nervous system (CNS) myelination, after induction by OLIG2, another oligodendroglial lineage determinant. 1,24][5] The aim of our study was to characterize the expression of SOX10 in a large cohort of adult and paediatric CNS tumours and to evaluate its potential use as a biomarker.
IHC for SOX10 (ICH010 clone; 1:50 dilution; Diagnomics, San Diego, CA, USA) and OLIG2 (Polyclonal; 1:500 dilution; Sigma-Aldrich, St. Louis, MO, USA) was undertaken retrospectively on 3-lm-thick sections of formalin-fixed, paraffin-embedded tissue samples, using an Omnis automate.Our study included a total of 683 cases of adult-and paediatric-type CNS tumours from different subtypes (gliomas, embryonal, and ependymal tumours with a morphomolecular diagnosis in accordance with the World Health Organization Classification of CNS tumours, including DNA-methylation profiling [v.12.8] when necessary; for details, see Table 1).The IHC tests were performed on whole sections in 487 cases and on TMA (tissue microarray) for 15 meningiomas, 123 ependymomas, 44 medulloblastomas, and 14 diffuse hemispheric gliomas, H3 G34-mutant.The nuclear immunostaining results for SOX10 and OLIG2 were scored (by ATE and OA) as positive (≥10% positive tumour cells) or negative (<10% positive tumour cells).OLIG2 staining was not performed for tumours that were not glial or glioneuronal tumours.In the case of a discrepancy between the two observations, another pathologist (P.V.) was solicited to conclude.
Our work is the first to evaluate the expression of SOX10 in a large cohort of molecularly defined CNS tumours.We confirm previous reports that demonstrated the use of SOX10 as a diagnostic marker to discriminate CNS NB from other embryonal tumours. 3,47][8] Interestingly, a subset of supratentorial ependymomas, ZFTA::RELA fusion-positive   3 all DNA-methylation proven diffuse leptomeningeal glioneuronal tumours from our cohort were immunopositive for SOX10 (Figure S1).Similarly, we showed that SOX10 was not expressed in oligodendrogliomas, IDH-mutant, and 1p/19qcodeleted, contrary to the literature. 5However, the conclusions in the aforementioned literature were made prior to the molecular era.Interestingly, SOX10 could help differentiate between the different subtypes of HGG in routine neuropathology.In paediatric-type HGG, SOX10 seems to be differentially expressed and can help distinguish DMG, EGFR-mutant from H3-mutant, and EZHIPoverexpressed.This observation is in line with the fact that DMG, EGFR-mutant are epigenetically separate from H3-mutant and EZHIP-overexpressed DMG and potentially stem from a distinct cell of origin. 10,11hese results need to be validated in a larger cohort of DMG.In hemispheric locations, SOX10 may help to distinguish diffuse paediatric-type HGG, RTK1 (which seems to express SOX10), from RTK2 and MYCN subtypes (both are always immunonegative for SOX10).
Concerning glioblastoma, molecular subtypes seem to differentially express SOX10 (positive in RTK1 and PF subtypes and negative in RTK2 and MES subtypes).These results are in line with a previous study suggesting SOX10 as a master regulator of glioblastoma subtypes. 9Through multiomic profiling, SOX10 was identified as a regulator of the RTK1 subtype and a loss of SOX10 was shown to cause a subtype switch from RTK1 to one analogous to the MES subtype.Similarly, in circumscribed gliomas, pleomorphic xanthoastrocytoma and high-grade astrocytoma with piloid features can also be distinguished by SOX10 expression.However, SOX10 shows poor sensitivity and specificity for glioneuronal and neuronal neoplasms; therefore, we do not recommend using it for these tumour types.

Table 1 .
Immunohistochemical results of OLIG2 and SOX10 in our cohort