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

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; David S Ziegler

doi:10.1093/neuonc/noaf061

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

Neuro Oncol. 2025 Sep 8;27(7):1849-1863. doi: 10.1093/neuonc/noaf061.

Authors

Marion K Mateos^{1

2

3}, Pamela Ajuyah¹, Noemi Fuentes-Bolanos^{1

2

3}, Sam El-Kamand¹, Paulette Barahona¹, Ann-Kristin Altekoester¹, Chelsea Mayoh^{1

2}, Holly Holliday^{1

2}, Jie Liu¹, Louise Cui¹, Elke Pfaff^{4

5

6

7}, Alan Mackay⁸, Adam C Resnick, Mark Pinese^{1

2}, Loretta M S Lau^{1

2

3}, Dong-Anh Khuong-Quang^{9

10}, Kimberly Dias¹, Catherine Goudie^{11

12}, Alison Salkeld^{13

14

15

16}, Jo Lynne Rokita^{17

18

19}, David T W Jones^{5

6

7}, Nikoleta Juretic²⁰, Elisha Hayden¹, Stefan M Pfister^{4

5

6}, Christof M Kramm²¹, Mirjam Blattner-Johnson^{5

6

7}, Nada Jabado^{22

23

20}, Maria Tsoli^{1

2}, Orazio Vittorio^{1

24}, Sabine Mueller^{25

26}, Yiran Guo^{17

18}, Katherine Tucker^{2

27}, Sebastian M Waszak^{28

29}, Sebastien Perreault³⁰, Chris Jones⁸, Marie Wong-Erasmus², Mark J Cowley^{1

2}, David S Ziegler^{1

2

3}

Affiliations

¹ Children's Cancer Institute Australia, Lowy Cancer Research Centre, Sydney, New South Wales, Australia.
² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, New South Wales, Australia.
³ Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁴ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
⁵ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Germany.
⁷ Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁸ Division of Molecular Pathology, The Institute of Cancer Research (ICR), Sutton, UK.
⁹ Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹⁰ Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia.
¹¹ Division of Hematology-Oncology, Department of Pediatrics, McGill University Health Centre, Montreal, Quebec, Canada.
¹² Department of Child Health and Human Development, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
¹³ Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.
¹⁴ Sydney West Radiation Oncology Network, Sydney, New South Wales, Australia.
¹⁵ Sydney West Translational Cancer Research Centre, Westmead, Australia.
¹⁶ School of Medicine, The University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, USA.
¹⁸ Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, USA.
¹⁹ Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, USA.
²⁰ Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
²¹ Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
²² Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
²³ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
²⁴ Department of Biomedical Sciences, UNSW Medicine & Health, UNSW Sydney, Sydney, New South Wales, Australia.
²⁵ Department of Neurology, Neurosurgery and Pediatrics, University of California San Francisco, San Francisco, California, USA.
²⁶ Department of Pediatrics, University of Zurich, Zurich, Switzerland.
²⁷ Hereditary Cancer Centre, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia.
²⁸ Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EFPL), Lausanne, Switzerland.
²⁹ Department of Neurology, University of California San Francisco, San Francisco, California, USA.
³⁰ Department of Neurosciences, Centre Hospitalier Universitaire Sainte-Justine, Université de Montreal, Montreal, Quebec, Canada.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.

Keywords: PARP inhibitor; diffuse midline glioma; germline variants; homologous recombination; pediatric.

MeSH terms

Adolescent
Biomarkers, Tumor* / genetics
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Child
Child, Preschool
Cohort Studies
Exome Sequencing
Female
Follow-Up Studies
Genetic Predisposition to Disease*
Germ-Line Mutation*
Glioma* / genetics
Glioma* / pathology
Humans
Infant
Male
Prognosis

Substances

Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding