English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/229733
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE
Exportar a otros formatos:


Role of POLE and POLD1 in familial cancer

AuthorsMur, Pilar; García-Mulero, Sandra; Valle, Jesús del; Magraner-Pardo, Lorena; Vidal, August; Pineda, Marta; Cinnirella, Giacomo; Martín-Ramos, Edgar; Pons, Tirso CSIC ORCID ; López-Doriga, Adriana; Belhadj, Sami; Feliubadaló, Lidia; Munoz-Torres, Pau M.; Navarro, Matilde; Grau, Elia; Darder, Esther; Llort, Gemma; Sanz, Judit; Ramón y Cajal, Teresa; Balmana, Judith; Brunet, Joan; Moreno, Victor; Piulats, Josep M.; Matías-Guiu, Xavier; Sanz-Pamplona, Rebeca; Aligué, Rosa; Capellá, Gabriel; Lázaro, Conxi; Valle, Laura
KeywordsPolymerase proofreading–associated polyposis
Exonuclease domain
Ultramutated phenotype
Hereditary colorectal cancer
Issue Date2020
PublisherSpringer Nature
CitationGenetics in Medicine 22: 2089-2100 (2020)
Abstract[Purpose]: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. [Methods]: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. [Results]: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. [Conclusions]: Polymerase proofreading–associated syndrome constitutes 0.1–0.4% of familial cancer cases, reaching 0.3–0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
Publisher version (URL)http://dx.doi.org/10.1038/s41436-020-0922-2
Appears in Collections:(CNB) Artículos
Files in This Item:
File Description SizeFormat 
Role_Mur_Art2020.pdf1,74 MBAdobe PDFThumbnail
Show full item record
Review this work

Related articles:

WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.