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Germline variant affecting p53β isoforms predisposes to familial cancer

Author

Listed:
  • 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
    Croatian Institute of Transfusion Medicine)

  • 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
    University of Bristol)

  • 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
    Netherlands Cancer Institute)

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.

Suggested Citation

  • 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 , 2024. "Germline variant affecting p53β isoforms predisposes to familial cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52551-8
    DOI: 10.1038/s41467-024-52551-8
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    References listed on IDEAS

    as
    1. Philip J. Law & Maria Timofeeva & Ceres Fernandez-Rozadilla & Peter Broderick & James Studd & Juan Fernandez-Tajes & Susan Farrington & Victoria Svinti & Claire Palles & Giulia Orlando & Amit Sud & Am, 2019. "Association analyses identify 31 new risk loci for colorectal cancer susceptibility," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    2. Nicholas Light & Mehdi Layeghifard & Ayush Attery & Vallijah Subasri & Matthew Zatzman & Nathaniel D. Anderson & Rupal Hatkar & Sasha Blay & David Chen & Ana Novokmet & Fabio Fuligni & James Tran & Ri, 2023. "Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
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