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
{"title":"国际儿童弥漫性中线胶质瘤患者队列的种系分析。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":"1849-1863"},"PeriodicalIF":13.4000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417819/pdf/","citationCount":"0","resultStr":"{\"title\":\"Germline analysis of an international cohort of pediatric diffuse midline glioma patients.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.</p>\",\"PeriodicalId\":19377,\"journal\":{\"name\":\"Neuro-oncology\",\"volume\":\" \",\"pages\":\"1849-1863\"},\"PeriodicalIF\":13.4000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417819/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuro-oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/neuonc/noaf061\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/neuonc/noaf061","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Germline analysis of an international cohort of pediatric diffuse midline glioma patients.
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.
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.
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