The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity.

Autor:	Labrousse G; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France., Vande Perre P; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France.; Oncogenetics Department, Institute Claudius Regaud, IUCT-Oncopole, Toulouse, France., Parra G; Center for Genomic Analysis, CNAG, Carrer de Baldiri Reixac 4, Barcelona, Spain., Jaffrelot M; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France.; Oncogenetics Department, Institute Claudius Regaud, IUCT-Oncopole, Toulouse, France.; Department of Digestive Oncology, IUCT Rangueil-Larrey, CHU de Toulouse, Toulouse, France., Leroy L; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France., Chibon F; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France., Escudie F; Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irene-Joliot-Curie, 31059Toulouse, France., Selves J; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France.; Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irene-Joliot-Curie, 31059Toulouse, France., Hoffmann JS; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France.; Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irene-Joliot-Curie, 31059Toulouse, France., Guimbaud R; Oncogenetics Department, Institute Claudius Regaud, IUCT-Oncopole, Toulouse, France.; Department of Digestive Oncology, IUCT Rangueil-Larrey, CHU de Toulouse, Toulouse, France., Lutzmann M; Cancer Research Center of Toulouse, CRCT, 2 Avenue Hubert Curien, 31000Toulouse, France.; Institute of Human Genetics, IGH, UMR 9002, Centre National de la Recherche Scientifique, University of Montpellier, 34396Montpellier, France.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2023 Mar 11; Vol. 5 (2), pp. zcad011. Date of Electronic Publication: 2023 Mar 11 (Print Publication: 2023).
DOI:	10.1093/narcan/zcad011
Abstrakt:	The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) removes misincorporated nucleotides, called proofreading. POLE-exonuclease mutations cause colorectal- and endometrial cancers with an extreme burden of single nucleotide substitutions. We recently reported that particularly the hereditary POLE exonuclease mutation N363K predisposes in addition to aggressive giant cell glioblastomas. We knocked-in this mutation homozygously into human cell lines and compared its properties to knock-ins of the likewise hereditary POLE L424V mutation and to a complete proofreading-inactivating mutation (exo-null). We found that N363K cells have higher mutation rates as both L424V- or exo-null mutant cells. In contrast to L424V cells, N363K cells expose a growth defect, replication stress and DNA damage. In non-transformed cells, these burdens lead to aneuploidy but macroscopically normal nuclei. In contrast, transformed N363K cells phenocopy the enlarged and disorganized nuclei of giant cell glioblastomas. Taken together, our data characterize a POLE exonuclease domain mutant that not only causes single nucleotide hypermutation, but in addition DNA damage and chromosome instability, leading to an extended tumor spectrum. Our results expand the understanding of the polymerase exonuclease domain and suggest that an assessment of both the mutational potential and the genetic instability might refine classification and treatment of POLE-mutated tumors. (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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