Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic TP53 germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biol...

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Published in:iScience 2024-12, Vol.27 (12), p.111296, Article 111296
Main Authors: Montellier, Emilie, Lemonnier, Nathanaël, Penkert, Judith, Freycon, Claire, Blanchet, Sandrine, Amadou, Amina, Chuffart, Florent, Fischer, Nicholas W., Achatz, Maria-Isabel, Levine, Arnold J., Goudie, Catherine, Malkin, David, Bougeard, Gaëlle, Kratz, Christian P., Hainaut, Pierre
Format: Article
Language:English
Subjects:
Genomics
Phenotyping
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Summary:Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic TP53 germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biological p53 functions. Correlations with LFS phenotypes were analyzed using the public germline TP53 mutation database and validated in three LFS clinical cohorts. Class A carriers recapitulated all phenotypic traits of fully penetrant LFS, whereas class B carriers showed a slightly less penetrant form dominated by specific cancers, consistent with the notion that these classes identify variants with distinct functional properties. Class C displayed a lower lifetime cancer risk associated with attenuated LFS features, consistent with the notion that these variants have hypomorphic features. Class D carriers showed low lifetime cancer risks inconsistent with LFS definitions. This classification of TP53 variants provides insights into structural/functional features causing pathogenicity. [Display omitted] •We sorted TP53 variants into 4 classes based on functional assays•We analyzed their correlations with cancer phenotypes in Li-Fraumeni syndrome•Each class is associated with distinct cancer risks and phenotypes•The classes underscore structural/functional features causing pathogenicity Genomics; Phenotyping
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.111296