Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors

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<sup>-6</sup>) 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.

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Journal
Acta Neuropathologica
Published
2025-09-12
DOI
https://doi.org/10.1007/s00401-025-02935-x
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors

Bianca Santomasso, Andrew Lin, Lisa Marie DeAngelis, Matthias A. Karajannis et al.
Acta Neuropathologica
Glioma Diagnosis and Treatment
article

Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors

Bianca Santomasso, Andrew Lin, Lisa Marie DeAngelis, Matthias A. Karajannis, Elena Pentsova, Robert J. Young, Anna F. Piotrowski, Tejus Bale, Lauren R. Schaff, Christian Grommes, Ingo K. Mellinghoff, Walid K. Chatila, Brandon S. Imber, Kenny Kwok Hei Yu, Igor T. Gavrilovic, Jessica Wilcox, Kate E. Therkelsen, P. Akella, Nikolaus Schultz, Michael F. Berger, Yelena M. Kemel, Miika M. Mehine, Thomas Kaley, Sameer Farouk Sait, Adrienne Ann Boire, Daniel M. Muldoon, Diana L. Mandelker, Jacqueline Stone, Shahiba Ogilvie, Marc K. Rosenblum, Craig Nolan, Anita S. Bowman, Zsofia Kinga Stadler, Subhiksha Nandakumar, Kevin B. Elmore, Viviane Tabar, Eli L. Diamond, Nelson S. Moss, Cameron Brennan, Chaitanya Bandlamudi, Yun-Te Lin
article en

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<sup>-6</sup>) 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.

Acta NeuropathologicaVol. 150(1)
Memorial Sloan Kettering Cancer Center (US), Molecular Oncology (United States) (US)
Openalex Percentile: Top 66%
Glioma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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