Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families : = Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases [epsilon] and [delta] in glioma families

Abstract: Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy

Object Details

• Alternative title: Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases [epsilon] and [delta] in glioma families
• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Acta Neuropathologica Communications. - 11, 1 (2023) , 184, ISSN: 2051-5960

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Weber, Christine A. M. ; Krönke, Nicole ; Volk, Valery ; Auber, Bernd ; Förster, Alisa ; Trost, Detlef ; Geffers, Robert ; Esmaeilzadeh, Majid ; Lalk, Michael ; Nabavi, Arya ; Samii, Amir ; Krauss, Joachim K. ; Feuerhake, Friedrich ; Hartmann, Christian ; Wiese, Bettina ; Brand, Frank ; Weber, Ruthild

Further information

• DOI: 10.1186/s40478-023-01689-5
• URN: urn:nbn:de:bsz:25-freidok-2425947
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:52 PM CET