Germline variant affecting p53β isoforms predisposes to familial cancer

Stephanie A. Schubert, Dina Ruano, Sebastien M. Joruiz, Jordy Stroosma, Nikolina Glavak, Anna Montali, Lia M. Pinto, Mar Rodríguez-Girondo, Daniela Q. C. M. Barge-Schaapveld, Maartje Nielsen, Bernadette P. M. Nesselrooij, Arjen R. Mensenkamp, Monique E. Leerdam, Thomas H. Sharp, Hans Morreau, Jean-Christophe Bourdon (), Noel F. C. C. Miranda () and Tom Wezel ()
Additional contact information
Stephanie A. Schubert: Leiden University Medical Center
Dina Ruano: Leiden University Medical Center
Sebastien M. Joruiz: University of Dundee
Jordy Stroosma: Leiden University Medical Center
Nikolina Glavak: University of Dundee
Anna Montali: University of Dundee
Lia M. Pinto: University of Dundee
Mar Rodríguez-Girondo: Leiden University Medical Center
Daniela Q. C. M. Barge-Schaapveld: Leiden University Medical Center
Maartje Nielsen: Leiden University Medical Center
Bernadette P. M. Nesselrooij: University Medical Center Utrecht
Arjen R. Mensenkamp: Radboud University Medical Center
Monique E. Leerdam: Leiden University Medical Center
Thomas H. Sharp: Leiden University Medical Center
Hans Morreau: Leiden University Medical Center
Jean-Christophe Bourdon: University of Dundee
Noel F. C. C. Miranda: Leiden University Medical Center
Tom Wezel: Leiden University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52551-8

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