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Article Dans Une Revue Neuropathology and Applied Neurobiology Année : 2021

GAB1 overexpression identifies Hedgehog‐activated anterior skull base meningiomas

Résumé

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 Hedgehog 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 SHH (Sonic Hedgehog) or IHH (Indian Hedgehog) 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 Hedgehog pathway. It could facilitate the identification of selected cases amenable to sequencing for hedgehog pathway genes as predictive markers for targeted therapy.
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Dates et versions

hal-03246116 , version 1 (02-06-2021)

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Julien Boetto, Julie Lerond, Matthieu Peyre, Suzanne Tran, Pauline Marijon, et al.. GAB1 overexpression identifies Hedgehog‐activated anterior skull base meningiomas. Neuropathology and Applied Neurobiology, 2021, ⟨10.1111/nan.12740⟩. ⟨hal-03246116⟩
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