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Pré-Publication, Document De Travail Année : 2023

Fine resolution clustering of TP53 variants into functional classes predicts cancer risks and spectra among germline variant carriers

Judith Penkert
Maria Isabel Achatz
Arnold Levine
Catherine Goudie
David Malkin
Christian Kratz
Pierre Hainaut

Résumé

ABSTRACT Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to a broad spectrum of cancers caused by pathogenic TP53 germline variants. We have used a clustering approach to assign missense variants to functional classes with distinct quantitative and qualitative features based on transcriptional activity in yeast assays. Genotype-phenotype correlations were analyzed using the germline TP53 mutation database (n= 3,446) and validated in three LFS clinical cohorts (n= 821). Carriers of class A variants recapitulated all traits of fully penetrant LFS (median age at first diagnosis = 28 years). Class B carriers showed a less penetrant form (median = 33 years, p < 0.05) dominated by adrenocortical and breast cancers. Class C or D carriers had attenuated phenotypes (median = 41 years, p < 0.001) with typical LFS cancers in C and mostly non-LFS cancers in D. This new classification provides insight into structural/functional features causing pathogenicity.

Dates et versions

hal-04451403 , version 1 (11-02-2024)

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Emilie Montellier, Nathanaël Lemonnier, Judith Penkert, Claire Freycon, Sandrine Blanchet, et al.. Fine resolution clustering of TP53 variants into functional classes predicts cancer risks and spectra among germline variant carriers. 2024. ⟨hal-04451403⟩
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