1. Germline variant affecting p53β isoforms predisposes to familial cancer.
- Author
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Schubert, Stephanie A., Ruano, Dina, Joruiz, Sebastien M., Stroosma, Jordy, Glavak, Nikolina, Montali, Anna, Pinto, Lia M., Rodríguez-Girondo, Mar, Barge-Schaapveld, Daniela Q. C. M., Nielsen, Maartje, van Nesselrooij, Bernadette P. M., Mensenkamp, Arjen R., van Leerdam, Monique E., Sharp, Thomas H., Morreau, Hans, Bourdon, Jean-Christophe, de Miranda, Noel F. C. C., and van Wezel, Tom
- Subjects
GENETIC variation ,FUNCTIONAL genomics ,LI-Fraumeni syndrome ,MOLECULAR diagnosis ,THYROID cancer - 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. Pathogenic germline variants in TP53 predispose to a variety of cancers, but variants solely affecting alternatively spliced isoforms of TP53 are understudied. Here, the authors identify a heterozygous stop-lost variant that specifically affects p53β isoforms and predisposes to familial cancer using germline whole-exome sequencing and functional genomics assays. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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