Deciphering dual clinical entities associated with <scp><i>TP53</i></scp> pathogenic variants: Insights from 53,085 <scp>HBOC</scp> panel analyses in French laboratories

TP53 is included in most cancer predisposition multigene panels, especially those exploring Hereditary Breast and Ovarian Cancer (HBOC) predisposition. The purpose of this study was to define the contribution of TP53 pathogenic variants (PV) to the HBOC phenotype by collecting genotypes and phenotypes of 398 patients harboring a TP53 variant identified by 53,085 HBOC panel sequencing in 15 French laboratories. Heterozygous TP53 variants were identified in 0.44% of HBOC panels, evenly distributed between PV and VUS. Breast cancers associated with TP53 were predominantly triple positive, particularly Her2+ breast cancer, in situ cancer, or phyllodes tumors (p < 0.0001 for both). Interestingly, TP53 PV were identified across all ages in breast cancer patients, with enrichment before 36y. We demonstrated that null variants were linked with the HBOC phenotype, and missense variants, especially with a dominant negative effect, with the LFS phenotype (p = 0.0096). Patients with breast cancer harboring null variants displayed an earlier age of onset compared to missense (p = 0.0030). Surprisingly, we identified, in late-onset cancer patients, TP53 hotspot PV usually identified in classic LFS, which underlines variable penetrance. Thus, this study suggests the existence of two phenotypic entities associated with TP53 PV: clinical LFS and TP53-related breast cancer. The type of TP53 variant, as well as modifying factors reflected in family history, may influence these phenotypes, and both should be considered to define the clinical follow-up of patients and relatives.

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Journal
International Journal of Cancer
Published
2025-06-11
DOI
https://doi.org/10.1002/ijc.35475
Citations
3
Primary Topic
Cancer-related Molecular Pathways
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article
Field-Weighted Citation Impact
3.14
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article

Deciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories

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3 citations
International Journal of Cancer
Cancer-related Molecular Pathways
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article

Deciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories

Laurent Castéra, Flavie Boulouard, Camille Charbonnier, Claude Houdayer, Lisa Golmard, Mathilde Gay‐Bellile, Dominique Vaur, Alexandre Perrier, Patrick R. Benusiglio, Hela Sassi, Jean‐Marie Ravel, Edwige Kasper, Gaëlle Bougeard, Etienne Rouleau, Nicolas Sévenet, Maud Branchaud, Pierre Vande Perre, Stéphanie Baert‐Desurmont, Emilie Bouvignies, Noémie Basset, Fanny Brayotel, Virginie Bubien, Paul Vilquin, Chrystelle Colas, Céline Bonnet, Jessica Le Gall, Mathis Lepage, Ahmed Bouras, Nathalie Parodi, Vincent Goussot, Olivier Caron, Valentin Dérangère, Alice Fiévet, Dominique Stoppa‐Lyonnet, Céline Garrec, Anna Lokchine, Juliette Albuisson, Marie Bidart, Ayman Al Saati, Marion Rolain, Adrien Buisson, Pascaline Berthet, Nadia Boutry‐Kryza, Marion Gauthier‐Villars, Jean‐Christophe Théry, Capucine Delnatte, Florence Coulet
article en
3 citations

Abstract

TP53 is included in most cancer predisposition multigene panels, especially those exploring Hereditary Breast and Ovarian Cancer (HBOC) predisposition. The purpose of this study was to define the contribution of TP53 pathogenic variants (PV) to the HBOC phenotype by collecting genotypes and phenotypes of 398 patients harboring a TP53 variant identified by 53,085 HBOC panel sequencing in 15 French laboratories. Heterozygous TP53 variants were identified in 0.44% of HBOC panels, evenly distributed between PV and VUS. Breast cancers associated with TP53 were predominantly triple positive, particularly Her2+ breast cancer, in situ cancer, or phyllodes tumors (p < 0.0001 for both). Interestingly, TP53 PV were identified across all ages in breast cancer patients, with enrichment before 36y. We demonstrated that null variants were linked with the HBOC phenotype, and missense variants, especially with a dominant negative effect, with the LFS phenotype (p = 0.0096). Patients with breast cancer harboring null variants displayed an earlier age of onset compared to missense (p = 0.0030). Surprisingly, we identified, in late-onset cancer patients, TP53 hotspot PV usually identified in classic LFS, which underlines variable penetrance. Thus, this study suggests the existence of two phenotypic entities associated with TP53 PV: clinical LFS and TP53-related breast cancer. The type of TP53 variant, as well as modifying factors reflected in family history, may influence these phenotypes, and both should be considered to define the clinical follow-up of patients and relatives.

International Journal of CancerVol. 157(5)
Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), Université de Bordeaux (FR), Inserm (FR), Université de Bourgogne (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Clermont Auvergne (FR), Université Paris Cité (FR), Université Paris Sciences et Lettres (FR), Centre Hospitalier Universitaire de Grenoble (FR), Institut Gustave Roussy (FR), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), Centre Georges François Leclerc (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Centre d’Investigation Clinique Innovation Technologique de Nancy (FR), Centre Léon Bérard (FR), Normandie Université (FR), Institut de Cancérologie de l'Ouest (FR), Pitié-Salpêtrière Hospital (FR), Centre François Baclesse (FR), Centre Jean Perrin (FR), Centre de Recherche en Cancérologie de Lyon (FR), Institut Claudius Regaud (FR), Institut Bergonié (FR), Laboratoire de Microbiologie et Génétique Moléculaires (FR), Institut Jean Godinot (FR), Centre Hospitalier Universitaire de Rouen (FR), Institut pour l'avancée des biosciences (FR), Centre Henri Becquerel, Nutrition-Génétique et Exposition aux Risques Environnementaux (FR), Imagerie Moléculaire et Stratégies Théranostiques, Génomique du cancer et du cerveau, BoRdeaux Institute of onCology (FR), Université de Rouen Normandie (FR), Institut Curie (FR), Université Grenoble Alpes (FR), Université de Lorraine (FR), Université de Caen Normandie (FR)
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Openalex Percentile: Top 8%
Cancer-related Molecular Pathways
3.14
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