Titel: Rare germline variants in the POLE and POLD1 genes in familial glioma
ID: P-CancG-032
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
BasEpi / CancG / CytoG

Referent: Christine A. M. Weber (Hannover/DE)

Abstract - Text


Understanding the genetic basis of brain tumor risk is far from complete. In search of rare germline alterations predisposing to glioma, we performed whole-exome sequencing on leukocyte DNA of 53 tumor families with at least one glioma case each. In two families, we identified rare heterozygous missense variants in the POLE gene that co-segregated with the tumor phenotype. Altogether, rare heterozygous POLE or POLD1 missense variants predicted to be deleterious were detected in eight patients of seven of 53 (13%) families. Rare variants in the exonuclease domain (ED) of POLE encoding the catalytic subunit of DNA polymerase ɛ and POLD1 encoding the catalytic subunit of DNA polymerase δ were previously shown to predispose to colorectal adenomas and carcinomas. The eight patients carrying POLE/POLD1 variants in our cohort were all affected by gliomas, i.e. glioblastomas, astrocytomas, and oligodendrogliomas. The other tumor types diagnosed in our families with POLE/POLD1 variants were colorectal and breast (occurring twice each) as well as small cell lung, prostate and uterus cancer, meningioma, and optic glioma (occurring once each). Tumors from patients with pathogenic variants in, and, possibly, outside the POLE/POLD1 ED are frequently characterized by an accumulation of somatic mutations, making these tumors susceptible to checkpoint blockade immunotherapy. Although all POLE/POLD1 variants identified in glioma patients here were located outside of the ED, we found evidence for hypermutation in 3 of 7 primary gliomas analyzed. For functional characterization, we generated a CRISPR/Cas9-mediated knockout of POLE or POLD1 in two cell lines. In a HPRT1 mutation assay, POLE-/- LN-229 glioblastoma cells displayed higher resistance to 6-thioguanine, which indicates an increased HPRT1 mutation rate compared to POLE+/+ cells. In ongoing experiments, the impact of the identified variants on polymerase function is being investigated by analysis of S-phase progression of POLE/POLD1 knockout cells after re-expression of POLE/POLD1 variants versus wildtype. Because very rare spinal metastases occurred in glioma patients carrying a POLE variant here and in a previous study, leading to the hypothesis that POLE variants may promote metastasis, we analyzed the DNA of two spinal metastases from other glioblastoma patients and identified a rare POLE variant in one case. In summary, we provide evidence for a potential role of rare POLE/POLD1 variants in glioma predisposition.