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
Affiliations
Emilie Montellier
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France
Nathanaël Lemonnier
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France
Judith Penkert
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; Department of Human Genetics, Hannover Medical School, Hannover, Germany
Claire Freycon
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France; Department of Pediatric Hematology-Oncology, Grenoble Alpes University Hospital, Grenoble, France; Department of Pediatrics, Division of Hematology-Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
Sandrine Blanchet
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France
Amina Amadou
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France; Department of Prevention Cancer Environment, Centre Léon Bérard, Lyon, France
Florent Chuffart
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France
Nicholas W. Fischer
Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Maria-Isabel Achatz
Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil
Arnold J. Levine
Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA
Catherine Goudie
Department of Pediatrics, Division of Hematology-Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
David Malkin
Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
Gaëlle Bougeard
University Rouen Normandie, Inserm U1245, Normandie University, CHU Rouen, Department of Genetics, F-76000 Rouen, France
Christian P. Kratz
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Pierre Hainaut
University Grenoble Alpes, Inserm 1209, CNRS 5309, Institute for Advanced Biosciences, F38000 Grenoble, France; Corresponding author
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.
