Journal Article

DKFZ-2025-03030

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.

Fernandez, N. R. ; Chang, Y. ; Nunes, N. M. ; Dimayacyac, J. R. ; Levine, A. ; Ringel, A. ; Negm, L. ; Ercan, A. B. ; Hess, J. M. ; Ahmad, O.DKFZ* ; Lee, C. ; Stengs, L. ; Bianchi, V. ; Edwards, M. ; Doherty, S. ; Chung, J. ; Nobre, L. ; Bennett, J. ; Dodgshun, A. J. ; Jones, D.DKFZ* ; Pfister, S.DKFZ* ; Villani, A. ; Malkin, D. ; Ramaswamy, V. ; Huang, A. ; Bouffet, E. ; Aronson, M. ; Dirks, P. B. ; Shlien, A. ; Getz, G. ; Maruvka, Y. E. ; Ertl-Wagner, B. ; Hawkins, C. ; Das, A. ; Tabori, U.

2026
Macmillan Publishers Limited, part of Springer Nature London

Abstract: 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.

Note: 2026 Jan;58(1):132-142

---

Contributing Institute(s):

1. Pädiatrische Gliomforschung (B360)
2. B062 Pädiatrische Neuroonkologie (B062)
3. DKTK HD zentral (HD01)

Research Program(s):

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

Appears in the scientific report 2025

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---