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

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

Authors:	Nandakumar, S.; Mehine, M.; Kemel, Y.; Bandlamudi, C.; Mandelker, D.; Rosenblum, M. K.; Bale, T.; Karajannis, M. A.; Sait, S. F.; Elmore, K. B.; Therkelsen, K. E.; Chatila, W. K.; Muldoon, D.; Young, R. J.; Imber, B. S.; Brennan, C.; Moss, N. S.; Yu, K. K. H.; Tabar, V.; Ogilvie, S.; Bowman, A.; Akella, P.; Lin, Y. T.; Gavrilovic, I. T.; Pentsova, E.; Schaff, L.; Stone, J.; Nolan, C.; Boire, A.; Grommes, C.; Santomasso, B. D.; Diamond, E. L.; Wilcox, J.; Piotrowski, A.; Kaley, T. J.; Deangelis, L. M.; Mellinghoff, I. K.; Berger, M.; Schultz, N.; Stadler, Z. K.; Lin, A. L.
Article Title:	Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors
Abstract:	<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 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 x 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.</p>
Keywords:	risk; li-fraumeni syndrome; lynch syndrome; mutations; framework; signatures; neurofibromatosis type 1; mismatch repair deficiency; american-college; medical genetics; cancer; cancer predisposition syndrome; predicts response; germline sequencing
Journal Title:	Acta Neuropathologica
Volume:	150
ISSN:	0001-6322
Publisher:	Springer
Date Published:	2025-09-12
Start Page:	27
Language:	English
ACCESSION:	WOS:001570219500001
DOI:	10.1007/s00401-025-02935-x
PROVIDER:	Clarivate Analytics Web of Science
PROVIDER:	wos
PMCID:	PMC12432092
PUBMED:	40938445
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Andrew L. Lin -- Source: Wos