TP53 variant clusters stratify phenotypic diversity in germline carriers and reveal an osteosarcoma-prone subgroup

Nicholas W. Fischer (), Noel Ong, Brianne Laverty, Pamela Psarianos, Camilla Giovino, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N. Maxwell, Christian P. Kratz, Ran Kafri and David Malkin ()
Additional contact information
Nicholas W. Fischer: The Hospital for Sick Children
Noel Ong: The Hospital for Sick Children
Brianne Laverty: The Hospital for Sick Children
Pamela Psarianos: The Hospital for Sick Children
Camilla Giovino: The Hospital for Sick Children
Noa Alon: The Hospital for Sick Children
Emilie Montellier: Université Grenoble Alpes
Pierre Hainaut: Université Grenoble Alpes
Kara N. Maxwell: Perelman School of Medicine at the University of Pennsylvania
Christian P. Kratz: Hannover Medical School
Ran Kafri: University of Toronto
David Malkin: The Hospital for Sick Children

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. This variability is thought to stem in part from the diverse functional impacts of TP53 variants, although the underlying mechanisms remain poorly understood and there is an unmet clinical need for effective risk stratification. Here, we apply unsupervised clustering to functional datasets and identify distinct TP53 variant groups with clinical relevance, including a monomeric subgroup enriched in osteosarcoma cases. In cellular validation assays, dermal fibroblasts from carriers of more functionally impaired variants exhibit increased metabolic growth rates, mirroring trends observed in cluster-stratified clinical outcomes. These findings demonstrate the feasibility of developing diagnostic assays to guide personalized cancer risk assessment. More broadly, our results show that nuances in TP53 dysfunction shape the germline TP53-related cancer susceptibility spectrum and provide a framework for functionally delineating variant carriers.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63528-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63528-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63528-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().