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

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 diff...

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Main Authors: Mateos, Marion (Author) , Ajuyah, Pamela (Author) , Fuentes-Bolanos, Noemi (Author) , El-Kamand, Sam (Author) , Barahona, Paulette (Author) , Altekoester, Ann-Kristin (Author) , Mayoh, Chelsea (Author) , Holliday, Holly (Author) , Liu, Jie (Author) , Cui, Louise (Author) , Pfaff, Elke (Author) , Mackay, Alan (Author) , Resnick, Adam C (Author) , Pinese, Mark (Author) , Lau, Loretta M S (Author) , Khuong-Quang, Dong-Anh (Author) , Dias, Kimberly (Author) , Goudie, Catherine (Author) , Salkeld, Alison (Author) , Rokita, Jo Lynne (Author) , Jones, David T. W. (Author) , Juretic, Nikoleta (Author) , Hayden, Elisha (Author) , Pfister, Stefan (Author) , Kramm, Christof M (Author) , Blattner-Johnson, Mirjam (Author) , Jabado, Nada (Author) , Tsoli, Maria (Author) , Vittorio, Orazio (Author) , Mueller, Sabine (Author) , Guo, Yiran (Author) , Tucker, Katherine (Author) , Waszak, Sebastian M (Author) , Perreault, Sebastien (Author) , Jones, Chris (Author) , Wong-Erasmus, Marie (Author) , Cowley, Mark J (Author) , Ziegler, David S (Author)
Format: Article (Journal)
Language:English
Published: July 2025
In: Neuro-Oncology
Year: 2025, Volume: 27, Issue: 7, Pages: 1849-1863
ISSN:1523-5866
DOI:10.1093/neuonc/noaf061
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/neuonc/noaf061
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Author Notes:Marion K. Mateos, Pamela Ajuyah, Noemi Fuentes-Bolanos, Sam El-Kamand, Paulette Barahona, Ann-Kristin Altekoester, Chelsea Mayoh, Holly Holliday, Jie Liu, Louise Cui, Elke Pfaff, Alan Mackay, Adam C. Resnick, Mark Pinese, Loretta M.S. Lau, Dong-Anh Khuong-Quang, Kimberly Dias, Catherine Goudie, Alison Salkeld, Jo Lynne Rokita, David T.W. Jones, Nikoleta Juretic, Elisha Hayden, Stefan M. Pfister, Christof M. Kramm, Mirjam Blattner-Johnson, Nada Jabado, Maria Tsoli, Orazio Vittorio, Sabine Mueller, Yiran Guo, Katherine Tucker, Sebastian M. Waszak, Sebastien Perreault, Chris Jones, Marie Wong-Erasmus, Mark J. Cowley, and David S. Ziegler
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Summary: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 the absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = .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 a 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.
Item Description:Veröffentlicht: 12. März 2025
Gesehen am 08.10.2025
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noaf061

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