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

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2025-03-12 DOI:10.1093/neuonc/noaf061

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

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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 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.

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

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.