IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA

• Verfasst von: Ahmad, Olfat [VerfasserIn]
• Verfasst von: Ahmad, Tahani [VerfasserIn]
• Verfasst von: Pfister, Stefan [VerfasserIn]
• Titel: IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA
• Titelzusatz: a systematic review
• Verf.angabe: Olfat Ahmad, Tahani Ahmad and Stefan M. Pfister
• E-Jahr: 2024
• Jahr: 09 February 2024
• Umfang: 20 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 20.06.2024
• Titel Quelle: Enthalten in: Molecular oncology
• Ort Quelle: Hoboken, NJ : John Wiley & Sons, Inc., 2007
• Jahr Quelle: 2024
• Band/Heft Quelle: (2024), Seite 1-20
• ISSN Quelle: 1878-0261
• DOI: doi:10.1002/1878-0261.13598
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: IDH-mutant glioma
• Sach-SW: immunogenicity
• Sach-SW: PMMRDIA
• K10plus-PPN: 1891660926

Abstract

In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.