TY - JOUR
T1 - Germline variant affecting p53β isoforms predisposes to familial cancer
AU - Schubert, Stephanie A.
AU - Ruano, Dina
AU - Joruiz, Sebastien M.
AU - Stroosma, Jordy
AU - Glavak, Nikolina
AU - Montali, Anna
AU - Pinto, Lia
AU - Rodríguez-Girondo, Mar
AU - Barge-Schaapveld, Daniela Q. C. M.
AU - Nielsen, Maartje
AU - van Nesselrooij, Bernadette P. M.
AU - Mensenkamp, Arjen R.
AU - van Leerdam, Monique E.
AU - Sharp, Thomas H.
AU - Morreau, Hans
AU - Bourdon, Jean-Christophe
AU - de Miranda, Noel F. C. C.
AU - van Wezel, Tom
N1 - © The Author(s) 2024
PY - 2024/9/18
Y1 - 2024/9/18
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-52551-8
DO - 10.1038/s41467-024-52551-8
M3 - Article
C2 - 39294166
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
M1 - 8208
ER -