Mateos Marion K, Ajuyah Pamela, Fuentes-Bolanos Noemi, El-Kamand Sam, Barahona Paulette, Altekoester Ann-Kristin, Mayoh Chelsea, Holliday Holly, Liu Jie, Cui Louise, Pfaff Elke, Mackay Alan, Resnick Adam C, Pinese Mark, Lau Loretta M S, Khuong-Quang Dong-Anh, Dias Kimberly, Goudie Catherine, Salkeld Alison, Rokita Jo Lynne, Jones David T W, Juretic Nikoleta, Hayden Elisha, Pfister Stefan M, Kramm Christof M, Blattner-Johnson Mirjam, Jabado Nada, Tsoli Maria, Vittorio Orazio, Mueller Sabine, Guo Yiran, Tucker Katherine, Waszak Sebastian M, Perreault Sebastien, Jones Chris, Wong-Erasmus Marie, Cowley Mark J, Ziegler David S
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney NSW, Australia.
Neuro Oncol. 2025 Mar 12. doi: 10.1093/neuonc/noaf061.
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.
驱动弥漫性中线胶质瘤（DMG）发生发展的因素尚不清楚。我们的研究旨在确定患有DMG的儿科患者中致病性/可能致病性（P/LP）种系变异的患病率。
我们组建了一个由252名患有DMG的儿科患者组成的国际队列，其中包括弥漫性脑桥内胶质瘤患者（n = 153），并对其进行种系全基因组或全外显子组测序。
我们在7.5%（19/252）的患者中发现了癌症易感基因中的P/LP种系变异。肿瘤特征有所不同，种系存在P/LP变异的患者与不存在该变异的患者相比，PI3K/mTOR通路中不存在体细胞驱动因素（P = 0.023）。P/LP种系变异在同源重组基因（n = 9；BRCA1、BRCA2、PALB2）和范可尼贫血基因（n = 4）中反复出现。体细胞研究结果表明，种系变异在至少1%的病例中确实促成了肿瘤发生。一名患有复发性DMG且带有致病性种系变异（BRCA2、FANCE）的患者对PARP和免疫检查点抑制表现出近乎完全的放射学反应。
我们的研究确定了儿科DMG中致病性种系变异的患病率，并表明一部分患者的肿瘤发生与此有关。
