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<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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月12日

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  • 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

摘要

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.