TY  - JOUR
AU  - Ahmad, Olfat
AU  - Ahmad, Tahani
AU  - Pfister, Stefan
TI  - IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA: a systematic review.
JO  - Molecular oncology
VL  - 18
IS  - 12
SN  - 1574-7891
CY  - Hoboken, NJ
PB  - John Wiley & Sons, Inc.
M1  - DKFZ-2024-00326
SP  - 2822-2841
PY  - 2024
N1  - 2024 Dec;18(12):2822-2841 / #EA:B062#LA:B062#
AB  - 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.
KW  - IDH-mutant glioma (Other)
KW  - PMMRDIA (Other)
KW  - immunogenicity (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38339779
DO  - DOI:10.1002/1878-0261.13598
UR  - https://inrepo02.dkfz.de/record/288068
ER  -