Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction.
POLE
colorectal cancer
glioblastoma
penetrance
polymerase proofreading-associated polyposis
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
04
12
2019
accepted:
27
04
2020
revised:
27
04
2020
pubmed:
20
5
2020
medline:
28
4
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
Identifiants
pubmed: 32424176
doi: 10.1038/s41436-020-0828-z
pii: S1098-3600(21)00719-X
doi:
Substances chimiques
Poly-ADP-Ribose Binding Proteins
0
DNA Polymerase II
EC 2.7.7.7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1533-1541Références
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