Rare germline variants contribute to glioma predisposition: Whole-genome analysis of a regional cohort of glioma patients.
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Rosenbaum A, Wibom C, Hammermeister Suger A, Pensch R, Roy A, Brännström T, Rentoft M, Forsberg-Nilsson K, Lindblad-Toh K, Lindström S, Dahlin AM, Melin B
Neurooncol Adv 8 (1) vdag038 [2026-02-12; online 2026-02-12]
Gliomas are the most common malignant primary tumor of the central nervous system and show a high mortality, particularly at higher grades. Cancer predisposition syndromes and common low-penetrance single nucleotide polymorphisms have been shown to contribute to glioma risk, but the contribution of rare germline variants remains incompletely understood. Here, we investigated rare germline variants in glioma patients. We performed whole-genome sequencing on 113 glioma patients from Northern Sweden, analyzing rare germline variants across 651 genes. Variants were compared to population controls (ACpop, gnomAD) and validated in TCGA glioma data, a UK Biobank glioma nested case-control study, and a separate cohort of 105 Swedish glioblastomas. 17.6% of glioma cases carried a Pathogenic or Likely Pathogenic (P/LP) variant within 1 of the 651 genes, and the number of alleles carrying a P/LP was significantly more than in the reference data (P = ). Many of the observed candidate genes also harbored P/LP variants in our Swedish validation cohort. Overall, gene-based comparison of rare coding variants indicated an enrichment in several genes, including 3.2 × 10 - 3TP53, CREBBP, and DNMT3A. Rare P/LP germline variants were more frequent among glioma patients than in the reference population within our predefined gene set. These results suggest a contribution of rare germline variants to glioma risk, particularly in genes involved in DNA repair. While several genes are indicated as enriched with rare variants, only TP53 validates across all 3 patient sets.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 41878702
DOI 10.1093/noajnl/vdag038
Crossref 10.1093/noajnl/vdag038
pmc: PMC13007284
pii: vdag038