Germline variant affecting p53β isoforms predisposes to familial cancer

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 canc...

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Published in:	Nature communications Vol. 15; no. 1; pp. 8208 - 15
Main Authors:	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., van Wezel, Tom
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-09-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/1 14/63 45 45/23 49/91 631/208/68 631/67/1347 631/67/1459/1843 631/67/1504/1885 631/80 96/109 96/44 Adult Alternative splicing Alternative Splicing - genetics Amino acids Breast Neoplasms - genetics Breast Neoplasms - metabolism Cancer Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Female Genetic diversity Genetic Predisposition to Disease Germ-Line Mutation Humanities and Social Sciences Humans Isoforms Li-Fraumeni syndrome Li-Fraumeni Syndrome - genetics Male Middle Aged multidisciplinary Neoplasms - genetics Neoplasms - metabolism Oligomerization p53 Protein Pedigree Protein Isoforms - genetics Protein Isoforms - metabolism Science Science (multidisciplinary) Thyroid Thyroid cancer Thyroid Cancer, Papillary - genetics Thyroid Cancer, Papillary - metabolism Thyroid Cancer, Papillary - pathology Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumorigenesis Whole genome sequencing
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Summary:	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.342Serext17) 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-52551-8