Germline variant affecting p53β isoforms predisposes to familial cancer.
Humans
Tumor Suppressor Protein p53
/ genetics
Protein Isoforms
/ genetics
Germ-Line Mutation
Female
Genetic Predisposition to Disease
Male
Pedigree
Li-Fraumeni Syndrome
/ genetics
Adult
Middle Aged
Thyroid Cancer, Papillary
/ genetics
Colorectal Neoplasms
/ genetics
Breast Neoplasms
/ genetics
Alternative Splicing
/ genetics
Neoplasms
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Sep 2024
18 Sep 2024
Historique:
received:
08
05
2020
accepted:
06
09
2024
medline:
19
9
2024
pubmed:
19
9
2024
entrez:
18
9
2024
Statut:
epublish
Résumé
Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53's transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition.
Identifiants
pubmed: 39294166
doi: 10.1038/s41467-024-52551-8
pii: 10.1038/s41467-024-52551-8
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Protein Isoforms
0
TP53 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8208Subventions
Organisme : Maag Lever Darm Stichting (Dutch Digestive Foundation)
ID : FP13-13
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2015-7664
Organisme : ZonMw (Netherlands Organisation for Health Research and Development)
ID : 016.176.l44
Informations de copyright
© 2024. The Author(s).
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