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Fine resolution clustering of TP53 variants into functional classes predicts cancer risks and spectra among germline variant carriers
Open accessPreprint — published as 10.1016/j.isci.2024.111296 · Paper page
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.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Montellier, E., Lemonnier, N., Penkert, J., Freycon, C., Blanchet, S., Amadou, A., Chuffart, F., Fischer, N., Achatz, M. I., Levine, A., Goudie, C., Malkin, D., Bougeard, G., Kratz, C., & Hainaut, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Medizinische Hochschule Hannover (DE)
- University of Toronto (CA)
- Hospital Sírio-Libanês (BR)
- Institute for Advanced Study (US)
- Montreal Children's Hospital (CA)
- Inserm (FR)
- Corresponding author
- Hainaut, Pierre
- ORCID
- Venue
- iScience
- Publisher
- openRxiv
- Published
- 2023-12-28
- Volume
- 27
- Issue
- 12
- Pages
- 111296-111296
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC11615613
- OpenAlex
- W4403973465
- Cited by
- 29
- References
- 1
- Citations by year
- 2026: 17 · 2025: 11 · 2024: 1
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Canadian Imperial Bank of Commerce
- Université Grenoble Alpes
- Bundesministerium für Bildung und Forschung (01GM2205A)
- Fondation ARC pour la Recherche sur le Cancer
- Terry Fox Research Institute
- Deutsche Kinderkrebsstiftung (DKS 2024.03)
- Horizon 2020 Framework Programme
- MSDAVENIR
- H2020 Marie Skłodowska-Curie Actions (846806)
- Cancéropôle Lyon Auvergne-Rhône-Alpes
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- Li-Fraumeni syndrome, TP53 germline variants, missense mutations, variant clustering, cancer susceptibility, cancer risk, penetrance, hypomorphic variants, variant pathogenicity, variant interpretation
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