{"doi":"10.1007/s00401-025-02935-x","title":"Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors","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.","journal":"Acta Neuropathologica","year":2025,"id":534701,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8821,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1030614,"name":"Miika Mehine","orcid":"0000-0003-0443-0625","position":1,"is_corresponding":false},{"id":335055,"name":"Yelena Kemel","orcid":"0000-0002-5042-5651","position":2,"is_corresponding":false},{"id":271416,"name":"Chaitanya Bandlamudi","orcid":"0000-0003-1108-4919","position":3,"is_corresponding":false},{"id":2235,"name":"Diana Mandelker","orcid":"0000-0003-4154-0567","position":4,"is_corresponding":false},{"id":236602,"name":"Marc K. 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