Subhiksha Nandakumar, Miika Mehine, Yelena Kemel, Chaitanya Bandlamudi, Diana Mandelker, Marc K. Rosenblum, Tejus Bale, Matthias A. Karajannis, Sameer Farouk Sait, Kevin B. Elmore, Kate E. Therkelsen, Walid K. Chatila, Daniel Muldoon, Robert J. Young, Brandon S. Imber, Cameron Brennan, Nelson S. Moss, Kenny K. H. Yu, Viviane Tabar, Shahiba Ogilvie, Anita Bowman, Pallavi Akella, Yun-Te Lin, Igor T. Gavrilovic, Elena Pentsova, Lauren Schaff, Jacqueline Stone, Craig Nolan, Adrienne Boire, Christian Grommes, Bianca D. Santomasso, Eli L. Diamond, Jessica Wilcox, Anna Piotrowski, Thomas J. Kaley, Lisa M. DeAngelis, Ingo K. Mellinghoff, Michael Berger, Nikolaus Schultz, Zsofia K. Stadler, Andrew L. Lin
{"title":"Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors","authors":"Subhiksha Nandakumar, Miika Mehine, Yelena Kemel, Chaitanya Bandlamudi, Diana Mandelker, Marc K. Rosenblum, Tejus Bale, Matthias A. Karajannis, Sameer Farouk Sait, Kevin B. Elmore, Kate E. Therkelsen, Walid K. Chatila, Daniel Muldoon, Robert J. Young, Brandon S. Imber, Cameron Brennan, Nelson S. Moss, Kenny K. H. Yu, Viviane Tabar, Shahiba Ogilvie, Anita Bowman, Pallavi Akella, Yun-Te Lin, Igor T. Gavrilovic, Elena Pentsova, Lauren Schaff, Jacqueline Stone, Craig Nolan, Adrienne Boire, Christian Grommes, Bianca D. Santomasso, Eli L. Diamond, Jessica Wilcox, Anna Piotrowski, Thomas J. Kaley, Lisa M. DeAngelis, Ingo K. Mellinghoff, Michael Berger, Nikolaus Schultz, Zsofia K. Stadler, Andrew L. Lin","doi":"10.1007/s00401-025-02935-x","DOIUrl":null,"url":null,"abstract":"<div><p>Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76–90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1–12.8%). Affected high- and moderate-penetrance genes included <i>BRCA2</i> (<i>n</i> = 11; 0.5%), <i>TP53</i> (<i>n</i> = 8; 0.4%), <i>NF1</i> (<i>n</i> = 8; 0.4%), <i>CHEK2</i> (<i>n</i> = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (<i>n</i> = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline <i>NF1</i> mutation, 7/8 tumors with a germline <i>TP53</i> alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including <i>BRCA2</i>-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (<i>p</i> = 3.5 × 10<sup>–6</sup>) and tumors with a monoallelic alteration (<i>p</i> = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02935-x.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-025-02935-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76–90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1–12.8%). Affected high- and moderate-penetrance genes included BRCA2 (n = 11; 0.5%), TP53 (n = 8; 0.4%), NF1 (n = 8; 0.4%), CHEK2 (n = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (n = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline NF1 mutation, 7/8 tumors with a germline TP53 alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including BRCA2-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (p = 3.5 × 10–6) and tumors with a monoallelic alteration (p = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.