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 Eleonora 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

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 Eleonora 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 (Corresponding Author)

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1849-1863
Journal	Neuro-Oncology
Volume	27
Issue number	7
DOIs	https://doi.org/10.1093/neuonc/noaf061
Publication status	Published - 8 Sept 2025
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords*

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

Field of Science*

3.2 Clinical medicine
3.1 Basic medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

Access to Document

10.1093/neuonc/noaf061Licence: CC BY

Cite this

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., Mackay, A., Resnick, A. C., Pinese, M., Lau, L. M. S., Khuong-Quang, D.-A., Dias, K., Goudie, C., Salkeld, A., ... Ziegler, D. S. (2025). Germline analysis of an international cohort of pediatric diffuse midline glioma patients. Neuro-Oncology, 27(7), 1849-1863. https://doi.org/10.1093/neuonc/noaf061

@article{fe8ea3838da14ad0a7d37ad927b5dbf3,

title = "Germline analysis of an international cohort of pediatric diffuse midline glioma patients",

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

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

note = "{\textcopyright} The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2025",

month = sep,

day = "8",

doi = "10.1093/neuonc/noaf061",

language = "English",

volume = "27",

pages = "1849--1863",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "7",

}

Mateos, MK, Ajuyah, P, Fuentes-Bolanos, N, El-Kamand, S, Barahona, P, Altekoester, A-K, Mayoh, C, Holliday, H, Liu, J, Cui, L, Pfaff, E, Mackay, A, Resnick, AC, Pinese, M, Lau, LMS, Khuong-Quang, D-A, Dias, K, Goudie, C, Salkeld, A, Rokita, JL, Jones, DTW, Juretic, N, Hayden, E, Pfister, SM, Kramm, CM, Blattner-Johnson, ME, Jabado, N, Tsoli, M, Vittorio, O, Mueller, S, Guo, Y, Tucker, K, Waszak, SM, Perreault, S, Jones, C, Wong-Erasmus, M, Cowley, MJ & Ziegler, DS 2025, 'Germline analysis of an international cohort of pediatric diffuse midline glioma patients', Neuro-Oncology, vol. 27, no. 7, pp. 1849-1863. https://doi.org/10.1093/neuonc/noaf061

TY - JOUR

T1 - Germline analysis of an international cohort of pediatric diffuse midline glioma patients

AU - Mateos, Marion K

AU - Ajuyah, Pamela

AU - Fuentes-Bolanos, Noemi

AU - El-Kamand, Sam

AU - Barahona, Paulette

AU - Altekoester, Ann-Kristin

AU - Mayoh, Chelsea

AU - Holliday, Holly

AU - Liu, Jie

AU - Cui, Louise

AU - Pfaff, Elke

AU - Mackay, Alan

AU - Resnick, Adam C

AU - Pinese, Mark

AU - Lau, Loretta M S

AU - Khuong-Quang, Dong-Anh

AU - Dias, Kimberly

AU - Goudie, Catherine

AU - Salkeld, Alison

AU - Rokita, Jo Lynne

AU - Jones, David T W

AU - Juretic, Nikoleta

AU - Hayden, Elisha

AU - Pfister, Stefan M

AU - Kramm, Christof M

AU - Blattner-Johnson, Mirjam Eleonora

AU - Jabado, Nada

AU - Tsoli, Maria

AU - Vittorio, Orazio

AU - Mueller, Sabine

AU - Guo, Yiran

AU - Tucker, Katherine

AU - Waszak, Sebastian M

AU - Perreault, Sebastien

AU - Jones, Chris

AU - Wong-Erasmus, Marie

AU - Cowley, Mark J

AU - Ziegler, David S

PY - 2025/9/8

Y1 - 2025/9/8

N2 - 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.

AB - 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.

KW - Humans

KW - Germ-Line Mutation

KW - Child

KW - Male

KW - Female

KW - Glioma/genetics

KW - Child, Preschool

KW - Adolescent

KW - Genetic Predisposition to Disease

KW - Brain Neoplasms/genetics

KW - Cohort Studies

KW - Biomarkers, Tumor/genetics

KW - Prognosis

KW - Infant

KW - Follow-Up Studies

KW - Exome Sequencing

UR - https://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:001465969100001

U2 - 10.1093/neuonc/noaf061

DO - 10.1093/neuonc/noaf061

M3 - Article

C2 - 40072012

SN - 1522-8517

VL - 27

SP - 1849

EP - 1863

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 7

ER -

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

Abstract

UN SDGs

Keywords*

Field of Science*

Publication Type*

Access to Document

Other files and links

Fingerprint

Cite this