TY  - JOUR
AU  - Fernandez, Nicholas R
AU  - Chang, Yuan
AU  - Nunes, Nuno M
AU  - Dimayacyac, Jose R
AU  - Levine, Adrian
AU  - Ringel, Amit
AU  - Negm, Logine
AU  - Ercan, Ayse Bahar
AU  - Hess, Julian M
AU  - Ahmad, Olfat
AU  - Lee, Caitlin
AU  - Stengs, Lucie
AU  - Bianchi, Vanessa
AU  - Edwards, Melissa
AU  - Doherty, Sheradan
AU  - Chung, Jiil
AU  - Nobre, Liana
AU  - Bennett, Julie
AU  - Dodgshun, Andrew J
AU  - Jones, David
AU  - Pfister, Stefan
AU  - Villani, Anita
AU  - Malkin, David
AU  - Ramaswamy, Vijay
AU  - Huang, Annie
AU  - Bouffet, Eric
AU  - Aronson, Melyssa
AU  - Dirks, Peter B
AU  - Shlien, Adam
AU  - Getz, Gad
AU  - Maruvka, Yosef E
AU  - Ertl-Wagner, Birgit
AU  - Hawkins, Cynthia
AU  - Das, Anirban
AU  - Tabori, Uri
TI  - Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.
JO  - Nature genetics
VL  - nn
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2025-03030
SP  - nn
PY  - 2025
N1  - epub
AB  - Primary mismatch-repair-deficient high-grade gliomas (priMMRD-HGG) are lethal tumors characterized by hypermutation, resistance to chemoradiation and variable response to immunotherapy. To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and patient outcomes, we analyzed genomic and clinical data from 162 priMMRD-HGG. Here we identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability-generating mechanisms, displaying an inverse correlation between point mutations and copy number alterations. MMRD signatures drive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD-HGG into a unique methylation cluster. DNA-polymerasemut priMMRD-HGG exhibit ultrahypermutation, an immune-hot microenvironment and immunotherapy responsiveness, whereas IDH1mut priMMRD-HGG are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of nonrandom mutagenesis patterns in cancer development, providing frameworks for targeted and immune-therapeutics.
LB  - PUB:(DE-HGF)16
C6  - pmid:41430480
DO  - DOI:10.1038/s41588-025-02420-x
UR  - https://inrepo02.dkfz.de/record/307431
ER  -