Germline analysis of an international cohort of pediatric diffuse midline glioma patients.

Mateos, Marion K; Lau, Loretta M S; Tucker, Katherine; Pfaff, Elke; Fuentes-Bolanos, Noemi; Liu, Jie; Cui, Louise; Khuong-Quang, Dong-Anh; Barahona, Paulette; Guo, Yiran; Jones, Chris; Ziegler, David S; Pfister, Stefan M; Hayden, Elisha; Ajuyah, Pamela; Goudie, Catherine; Jabado, Nada; Salkeld, Alison; Mueller, Sabine; Mackay, Alan; Dias, Kimberly; Jones, David T W; Vittorio, Orazio; El-Kamand, Sam; Blattner-Johnson, Mirjam; Waszak, Sebastian M; Pinese, Mark; Wong-Erasmus, Marie; Juretic, Nikoleta; Resnick, Adam C; Mayoh, Chelsea; Altekoester, Ann-Kristin; Perreault, Sebastien; Tsoli, Maria; Rokita, Jo Lynne; Holliday, Holly; Cowley, Mark J; Kramm, Christof M

doi:10.1093/neuonc/noaf061

Journal Article

DKFZ-2025-00544

Germline analysis of an international cohort of pediatric diffuse midline glioma patients.

Mateos, M. K. ; Ajuyah, P. ; Fuentes-Bolanos, N. ; El-Kamand, S. ; Barahona, P. ; Altekoester, A.-K. ; Mayoh, C. ; Holliday, H. ; Liu, J. ; Cui, L. ; Pfaff, E.DKFZ* ; Mackay, A. ; Resnick, A. C. ; Pinese, M. ; Lau, L. M. S. ; Khuong-Quang, D.-A. ; Dias, K. ; Goudie, C. ; Salkeld, A. ; Rokita, J. L. ; Jones, D. T. W.DKFZ* ; Juretic, N. ; Hayden, E. ; Pfister, S. M.DKFZ* ; Kramm, C. M. ; Blattner-Johnson, M.DKFZ* ; Jabado, N. ; Tsoli, M. ; Vittorio, O. ; Mueller, S. ; Guo, Y. ; Tucker, K. ; Waszak, S. M. ; Perreault, S. ; Jones, C. ; Wong-Erasmus, M. ; Cowley, M. J. ; Ziegler, D. S.

2025
Oxford Univ. Press Oxford

Neuro-Oncology 27(7), 1849-1863 (2025) [10.1093/neuonc/noaf061]

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Please use a persistent id in citations: doi:10.1093/neuonc/noaf061

Abstract: Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG.We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n=153), with germline whole genome or whole exome sequencing.We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = 0.023). P/LP germline variants were recurrent in homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed near-complete radiological response to PARP and immune checkpoint inhibition.Our study determined the prevalence of pathogenic germline variants in pediatric DMG, and suggests a role in tumorigenesis for a subset of patients.

Keyword(s): PARP inhibitor ; diffuse midline glioma ; germline variants ; homologous recombination ; pediatric