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

Emilie Montellier; Nathanaël Lemonnier; Judith Penkert; Claire Freycon; Sandrine Blanchet; Amina Amadou; Florent Chuffart; Nicholas W Fischer; Maria-Isabel Achatz; Arnold J Levine; Catherine Goudie; David Malkin; Gaëlle Bougeard; Christian P Kratz; Pierre Hainaut

doi:10.1016/j.isci.2024.111296

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

iScience. 2024 Nov 1;27(12):111296. doi: 10.1016/j.isci.2024.111296. eCollection 2024 Dec 20.

Authors

Emilie Montellier¹, Nathanaël Lemonnier¹, Judith Penkert^{2

3}, Claire Freycon^{1

4

5}, Sandrine Blanchet¹, Amina Amadou^{1

6}, Florent Chuffart¹, Nicholas W Fischer⁷, Maria-Isabel Achatz⁸, Arnold J Levine⁹, Catherine Goudie⁵, David Malkin^{7

10}, Gaëlle Bougeard¹¹, Christian P Kratz², Pierre Hainaut¹

Affiliations

¹ University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France.
² Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
³ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁴ Department of Pediatric Hematology-Oncology, Grenoble Alpes University Hospital, Grenoble, France.
⁵ Department of Pediatrics, Division of Hematology-Oncology, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
⁶ Department of Prevention Cancer Environment, Centre Léon Bérard, Lyon, France.
⁷ Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁸ Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil.
⁹ Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA.
¹⁰ Division of Hematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
¹¹ University Rouen Normandie, Inserm U1245, Normandie University, CHU Rouen, Department of Genetics, F-76000 Rouen, France.

Abstract

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.

Keywords: Genomics; Phenotyping.