Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.

Autor: Rocque MJ; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway.; Department of Medical Genetics, St. Olavs Hospital, 7030, Trondheim, Norway., Leipart V; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway.; Faculty of Environmental Sciences and Natural Resource Management, Norwegian University of Life Sciences, NMBU, 1432, Ås, Norway., Kumar Singh A; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway.; Department of Medical Genetics, St. Olavs Hospital, 7030, Trondheim, Norway., Mur P; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Olsen MF; Department of Medical Genetics, St. Olavs Hospital, 7030, Trondheim, Norway., Engebretsen LF; Department of Medical Genetics, St. Olavs Hospital, 7030, Trondheim, Norway., Martin-Ramos E; Department of Biomedical Sciences, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain., Aligué R; Department of Biomedical Sciences, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain., Sætrom P; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway.; Department of Computer and Information Science, NTNU-Norwegian University of Science and Technology, 7491, Trondheim, Norway.; Bioinformatics Core Facility-BioCore, NTNU-Norwegian University of Science and Technology, 7491, Trondheim, Norway.; K.G. Jebsen Center for Genetic Epidemiology, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway., Valle L; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Drabløs F; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway., Otterlei M; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway., Sjursen W; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, 7030, Trondheim, Norway. wenche.sjursen@ntnu.no.; Department of Medical Genetics, St. Olavs Hospital, 7030, Trondheim, Norway. wenche.sjursen@ntnu.no.
Jazyk: angličtina
Zdroj: Molecular genetics and genomics : MGG [Mol Genet Genomics] 2023 May; Vol. 298 (3), pp. 555-566. Date of Electronic Publication: 2023 Mar 01.
DOI: 10.1007/s00438-023-02000-w
Abstrakt: The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of POLE and POLD1, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers. In 2015, we reported the likely pathogenic (class 4) germline POLE c.1373A > T p.(Tyr458Phe) variant and we have now characterized this variant to verify that it is a class 5 pathogenic variant. For this purpose, we investigated (1) mutator phenotype in tumors from two carriers, (2) mutation frequency in cell-based mutagenesis assays, and (3) structural consequences based on protein modeling. Whole-exome sequencing of two tumors identified an ultra-mutator phenotype with a predominance of base substitutions, the majority of which are C > T. A SupF mutagenesis assay revealed increased mutation frequency in cells overexpressing the variant of interest as well as in isogenic cells encoding the variant. Moreover, exonuclease repair yeast-based assay supported defect in proofreading activity. Lastly, we present a homology model of human POLE to demonstrate structural consequences leading to pathogenic impact of the p.(Tyr458Phe) mutation. The three lines of evidence, taken together with updated co-segregation and previously published data, allow the germline variant POLE c.1373A > T p.(Tyr458Phe) to be reclassified as a class 5 variant. That means the variant is associated with PPAP.
(© 2023. The Author(s).)
Databáze: MEDLINE
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