# Germline variants in ATM, BRCA2, other cancer predisposition and novel candidate genes are implicated in glioma risk in adult glioma patients with a familial or personal history of tumors

## TL;DR

This study finds that germline variants in cancer-related genes like ATM and BRCA2 are linked to glioma risk in patients with a family or personal tumor history.

## Contribution

The study identifies novel and known cancer predisposition genes associated with glioma risk in patients with tumor histories.

## Key findings

- Germline variants in DNA damage response genes like ATM and BRCA2 were found in 23% of glioma patients with tumor histories.
- ATM variants were linked to younger diagnosis age and IDH-mutant astrocytoma, while BRCA2 variants were enriched in glioma patients.
- Some patients with germline variants may benefit from targeted therapies like PARP or immune checkpoint inhibitors.

## Abstract

Familial occurrence of gliomas has been reported in around 5% of patients. Studies on the genetic landscape of glioma predisposition are scarce. Here, leukocyte DNA of 213 adult glioma patients with a familial and/or personal tumor history from 206 families was subjected to whole-exome sequencing. Germline variants (GVs) were analyzed using two approaches: (1) GVs in 164 established cancer predisposition genes (CPGs) or suspected glioma risk genes were extracted and classified; (2) the enrichment of genes with loss-of-function or deleterious missense GVs that were ultrarare or ClinVar likely pathogenic/pathogenic in the glioma versus a control cohort (n = 391) was determined. In 23% (48/213) of glioma patients with a familial/personal tumor history, GVs predicted to be deleterious in CPGs were detected. Of the mutated CPGs, 37% were involved in DNA damage response, including ATM, BRCA2, PMS2, POLE. ATM GVs (n = 6) preferentially predisposed to IDH-mutant astrocytoma (P = 0.007) in patients that were significantly younger at diagnosis than patients without GVs (P = 0.022). BRCA2 GVs (n = 5) were also significantly enriched in glioma patients in approach 2 (P = 0.005). The other mutated CPGs, glioma risk or enriched novel genes play roles in diverse processes, including metabolism and signal transduction. Syn-/metachronous non-brain tumors were diagnosed in 29% of glioma patients with GVs. In 11% of patients, the identified CPG GVs potentially sensitized to targeted therapies, such as PARP, immune checkpoint, or EGFR inhibitors. In conclusion, our study identifies CPGs and novel genes relevant in germline testing of glioma patients with a familial/personal tumor history, possibly resulting in targeted treatment options.

The online version contains supplementary material available at 10.1007/s00401-025-02972-6.