Journal Article (Review Article)

DKFZ-2024-00326

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA: a systematic review.

Ahmad, O. (First author)DKFZ* ; Ahmad, T. ; Pfister, S. (Last author)DKFZ*

2024
John Wiley & Sons, Inc. Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/1878-0261.13598

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.

Keyword(s): IDH-mutant glioma ; PMMRDIA ; immunogenicity

Note: 2024 Dec;18(12):2822-2841 / #EA:B062#LA:B062#

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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