GAB1 overexpression identifies hedgehog‐activated anterior skull base meningiomas

Aims Mutations activating the hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh‐activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh‐activated meningiomas. Methods GAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas. Results Using an expression score ranging from 0 to 400, we show that a cut‐off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hh‐independent meningiomas. We describe a large series of 32 SMO‐mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co‐exclusive sonic hedgehog (SHH) or Indian hedgehog (IHH) overexpression independent of the mutations. Conclusion The assessment of GAB1 expression by an immunohistochemical score is a fast and cost‐efficient tool to screen anterior skull base meningiomas for activation of the Hh pathway. It could facilitate the identification of selected cases amenable to sequencing for Hh pathway genes as predictive markers for targeted therapy. Graphical The authors analysed a large cohort of anterior skull base meningiomas by successive methods: GAB1 immunohistochemistry, SMO Sanger sequencing, NGS genotyping and assessment of hedgehog pathway activation by RT‐qPCR. They showed that GAB1 immunohistochemistry is a powerful surrogate marker of hedgehog‐activated meningiomas. This study dissects the characteristics of hedgehog‐activated meningiomas, provides a cost‐efficient and available tool to identify them, and paves the way for a more efficient inclusion of patients in clinical trials of targeted therapies blocking the hedgehog pathway.