# Rare germline variants contribute to glioma predisposition: Whole-genome analysis of a regional cohort of glioma patients

## TL;DR

This study finds that rare genetic variants in specific genes may increase the risk of developing gliomas, a type of brain cancer.

## Contribution

The study identifies rare germline variants in glioma patients and shows their potential role in cancer predisposition.

## Key findings

- 17.6% of glioma cases had pathogenic or likely pathogenic variants in 651 genes.
- Rare variants were more frequent in glioma patients than in reference populations.
- TP53 was the only gene with consistent validation across all three patient sets.

## Abstract

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 = 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.

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.