TY - JOUR
T1 - Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors
AU - Nandakumar, Subhiksha
AU - Mehine, Miika
AU - Kemel, Yelena
AU - Bandlamudi, Chaitanya
AU - Mandelker, Diana
AU - Rosenblum, Marc K.
AU - Bale, Tejus
AU - Karajannis, Matthias A.
AU - Sait, Sameer Farouk
AU - Elmore, Kevin B.
AU - Therkelsen, Kate E.
AU - Chatila, Walid K.
AU - Muldoon, Daniel
AU - Young, Robert J.
AU - Imber, Brandon S.
AU - Brennan, Cameron
AU - Moss, Nelson S.
AU - Yu, Kenny K.H.
AU - Tabar, Viviane
AU - Ogilvie, Shahiba
AU - Bowman, Anita
AU - Akella, Pallavi
AU - Lin, Yun Te
AU - Gavrilovic, Igor T.
AU - Pentsova, Elena
AU - Schaff, Lauren
AU - Stone, Jacqueline
AU - Nolan, Craig
AU - Boire, Adrienne
AU - Grommes, Christian
AU - Santomasso, Bianca D.
AU - Diamond, Eli L.
AU - Wilcox, Jessica
AU - Piotrowski, Anna
AU - Kaley, Thomas J.
AU - DeAngelis, Lisa M.
AU - Mellinghoff, Ingo K.
AU - Berger, Michael
AU - Schultz, Nikolaus
AU - Stadler, Zsofia K.
AU - Lin, Andrew L.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
KW - Cancer predisposition syndrome
KW - Germline sequencing
KW - Li-Fraumeni syndrome
KW - Lynch syndrome
KW - Neurofibromatosis type 1
UR - https://www.scopus.com/pages/publications/105015789092
U2 - 10.1007/s00401-025-02935-x
DO - 10.1007/s00401-025-02935-x
M3 - Article
C2 - 40938445
AN - SCOPUS:105015789092
SN - 0001-6322
VL - 150
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
M1 - 27
ER -