Abstract Background Gliomas are the most common malignant primary tumor of the central nervous system (CNS) and show a high mortality, particularly at higher grades. Cancer predisposition syndromes and common low penetrance single nucleotide polymorphisms (SNPs) 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. Methods We performed whole-genome sequencing (WGS) 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. Results 17.6% of glioma cases carried a Pathogenic or Likely Pathogenic (P/LP) variant within one of the 651 genes, and number of alleles carrying a P/LP was significantly more than in the reference data (p = 3.2 × 10-3). 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 TP53, CREBBP, and DNMT3A. Conclusions Rare P/LP germline variants were more frequent among glioma patients than in 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 enriched with rare variants, only TP53 validates across all three patient sets.
Rosenbaum et al. (Wed,) studied this question.