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| Home > Articles > Published articles > Role of POLE and POLD1 in familial cancer |
(Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Cáncer) (Consell Superior d'Investigacions Científiques) (Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Cáncer) (Hospital Universitari de Bellvitge) (Institut d'Investigació Biomèdica Sant Pau) (Hospital Universitari Vall d'Hebron) (Institut Català d'Oncologia) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Centro de Investigación Biomédica en Red de Cáncer) (Centro de Investigación Biomédica en Red de Cáncer) (Centro de Investigación Biomédica en Red de Cáncer)| Date: | 2020 |
| Abstract: | 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. 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. 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. 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. |
| Grants: | Ministerio de Economía y Competitividad SAF2015-68016-R Ministerio de Economía y Competitividad PI16/00563 Ministerio de Economía y Competitividad PI16/00588 Ministerio de Economía y Competitividad PI14/00613 Instituto de Salud Carlos III PI19/00553 Ministerio de Economía y Competitividad CB16/12/00234 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Exonuclease domain ; Hereditary colorectal cancer ; Polymerase proofreading-associated polyposis ; PPAP ; Ultramutated phenotype |
| Published in: | Genetics in medicine, Vol. 22 Núm. 12 (december 2020) , p. 2089-2100, ISSN 1530-0366 |
