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Title: Role of POLE and POLD1 in familial cancer
Author: Mur, Pilar
García Mulero, Sandra
Valle, Jesús del
Magraner Pardo, Lorena
Vidal-Bel, August
Pineda Riu, Marta
Cinnirella, Giacomo
Martín Ramos, Edgar
Pons, Tirso
López Dóriga Guerra, Adriana
Belhadj, Sami
Feliubadaló i Elorza, Maria Lídia
Muñoz Torres, Pau M.
Navarro, Matilde
Grau Garcés, Èlia
Darder, Esther
Llort, Gemma
Sanz, Judit
Ramón y Cajal, Teresa
Balmaña, Judith
Brunet, Joan
Moreno Aguado, Víctor
Piulats, Josep M.
Matias-Guiu, Xavier
Sanz Pamplona, Rebeca
Aligué i Alemany, Rosa Maria
Capellá, G. (Gabriel)
Lázaro García, Conxi
Valle, Laura
Keywords: Càncer colorectal
Càncer d'endometri
Malalties hereditàries
Colorectal cancer
Endometrial cancer
Genetic diseases
Issue Date: 14-Aug-2020
Publisher: American College of Medical Genetics and Genomics
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.
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It is part of: Genetics in Medicine, 2020
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ISSN: 1098-3600
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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