Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in VSports app下载. gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2020 Dec;22(12):2089-2100.
doi: 10.1038/s41436-020-0922-2. Epub 2020 Aug 14.

VSports - Role of POLE and POLD1 in familial cancer

Pilar Mur  1   2   3 , Sandra García-Mulero  2   4 , Jesús Del Valle  1   2   3 , Lorena Magraner-Pardo  5 , August Vidal  6 , Marta Pineda  1   2   3 , Giacomo Cinnirella  1   2 , Edgar Martín-Ramos  7 , Tirso Pons  8 , Adriana López-Doriga  2   4   9 , Sami Belhadj  1   2 , Lidia Feliubadaló  1   2   3 , Pau M Munoz-Torres  1   2 , Matilde Navarro  1   2   3 , Elia Grau  1   2 , Esther Darder  10 , Gemma Llort  11   12 , Judit Sanz  13 , Teresa Ramón Y Cajal  14 , Judith Balmana  15 , Joan Brunet  1   2   3   10 , Victor Moreno  2   4   9   16 , Josep M Piulats  2   3   17 , Xavier Matías-Guiu  2   3   6 , Rebeca Sanz-Pamplona  2   4   9 , Rosa Aligué  7 , Gabriel Capellá  1   2   3 , Conxi Lázaro  1   2   3 , Laura Valle  18   19   20
Affiliations

Role of POLE and POLD1 in familial cancer

Pilar Mur et al. Genet Med. 2020 Dec.

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. VSports手机版.

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 V体育安卓版. .

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 V体育ios版. 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 VSports最新版本. 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. .

Keywords: PPAP; exonuclease domain; hereditary colorectal cancer; polymerase proofreading–associated polyposis; ultramutated phenotype V体育平台登录. .

PubMed Disclaimer

Conflict of interest statement (VSports注册入口)

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Schematic representation of the characteristics of the cohorts analyzed in this study, prevalence of (likely) pathogenic variants in cancer-predisposing genes, and results of the current study for exonuclease domain (ED) missense variants in POLE and POLD1.
BC breast cancer, BrC brain tumor, CRC colorectal cancer, EC endometrial cancer, GC gastric cancer, HBC hereditary breast cancer, HBOC hereditary breast and ovarian cancer, HOC hereditary ovarian cancer, HNPCC hereditary nonpolyposis colorectal cancer, LF Li–Fraumeni syndrome, LP likely pathogenic, OC ovarian cancer, PPAP polymerase proofreading–associated polyposis, VUS variant of unknown significance.
Fig. 2
Fig. 2. Functional analysis carried out in Schizosaccharomyces pombe for variants located within (or close to) the POLE exonuclease domain (ED).
(a) Alignment of human POLE and their homolog in yeast (Pol2). The identified variants are highlighted in yellow (conserved residues) and the POLE p.Leu424Val, used as positive control, in green. ED is depicted in red (human: residues 268–471, yeast: residues 98–428) and its sequence motifs are shaded in gray. (b) Left panel: box plots showing mutation rates of ade6-485 S. pombe (number of colonies) for pol2 wildtype (WT, negative control), ED mutation-positive control (pol2-Leu425Val; C+) and the corresponding variants. Right panel: fold rate increase relative to the median number of revertants in the WT. Data obtained from two independent experiments performed in triplicate. *p value = 0.01, **p value = 0.01–0.001, and ***p value < 0.001 indicate the differences with the WT clone, and were calculated using the Mann–Whitney nonparametric test.
Fig. 3
Fig. 3. Structural representation of human POLE and POLD1 and location of the ED variants identified in the current study.
(a) 3D structure of POLE. (b) 3D structure of POLD1. Single-stranded DNA from the aligned bacteriophage T4 polymerase complex (PDB ID: 1NOY) is shown in yellow. Variants in the DNA binding pocket are highlighted in red.
Fig. 4
Fig. 4. Somatic analysis performed in tumors from POLE/POLD1 variant carriers.
(a) Tumor features including mismatch repair (MMR) deficiency status and mutational burden (hypermutation was considered when the tumor had more than 10 exonic Mut/Mb). aHigh-grade serous ovarian cancer. bIntestinal origin. cMicrosatellite instability (MSI) classification using Bethesda panel. C+, positive controls, i.e., tumors from carriers of variants affecting the POLE/POLD1 ED previously classified as pathogenic. (b) Mutational signature contribution (DeconstructSigs) for hyper/ultramutated tumors (>10 Mut/Mb). CRC colorectal cancer.
See this image and copyright information in PMC

References

    1. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136–144. - "VSports最新版本" PMC - PubMed
    1. Valle L, Hernández-Illán E, Bellido F, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014;23:3506–3512. - PubMed
    1. Rohlin A, Eiengård F, Lundstam U, et al. GREM1 and POLE variants in hereditary colorectal cancer syndromes. Genes Chromosomes Cancer. 2016;55:95–106. - PMC (V体育官网入口) - PubMed
    1. Elsayed FA, Kets CM, Ruano D, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet. 2015;23:1080–1084. - PMC - PubMed
    1. Spier I, Holzapfel S, Altmüller J, et al. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int J Cancer. 2015;137:320–331. - PubMed

Publication types

Substances