CoChat
Sign Up
Cited by 29Cancer-related Molecular PathwaysGenomics and Rare DiseasesGenetic factors in colorectal cancer

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

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

Open access
Montellier, Emilie, Lemonnier, Nathanaël, Penkert, Judith, Freycon, Claire, Blanchet, Sandrine, Amadou, Amina, Chuffart, Florent, Fischer, Nicholas W., Achatz, Maria-Isabel, Levine, Arnold J., Goudie, Catherine, Malkin, David, Bougeard, Gaëlle, Kratz, Christian P., Hainaut, Pierre·2024·iScience
DOI 10.1016/j.isci.2024.111296PMC PMC11615613

Published version of a preprint

Open this paper in CoChat — free account

Abstract

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.isci.2024.111296

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 27

  1. Amadou, 2018, Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome, Curr. Opin. Oncol., 30, 23, 10.1097/CCO.0000000000000423 · DOI
  2. Li, 1988, A cancer family syndrome in twenty-four kindreds, Cancer Res., 48, 5358
  3. Frebourg, 2020, Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes, Eur. J. Hum. Genet., 28, 1379, 10.1038/s41431-020-0638-4 · DOI
  4. Kratz, 2021, Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis, JAMA Oncol., 7, 1800, 10.1001/jamaoncol.2021.4398 · DOI
  5. Kastenhuber, 2017, Putting p53 in Context, Cell, 170, 1062, 10.1016/j.cell.2017.08.028 · DOI · Paper page
  6. Levine, 2020, p53: 800 million years of evolution and 40 years of discovery, Nat. Rev. Cancer, 20, 471, 10.1038/s41568-020-0262-1 · DOI
  7. Hainaut, 2016, Somatic TP53 Mutations in the Era of Genome Sequencing, Cold Spring Harb. Perspect. Med., 6, 10.1101/cshperspect.a026179 · DOI
  8. Stein, 2020, Mutant p53 oncogenicity: dominant-negative or gain-of-function?, Carcinogenesis, 41, 1635, 10.1093/carcin/bgaa117 · DOI
  9. Kato, 2003, Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis, Proc. Natl. Acad. Sci. USA, 100, 8424, 10.1073/pnas.1431692100 · DOI
  10. Kotler, 2018, A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation, Mol. Cell, 71, 178, 10.1016/j.molcel.2018.06.012 · DOI
  11. Fortuno, 2021, Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants, Hum. Mutat., 42, 223, 10.1002/humu.24152 · DOI
  12. de Andrade, 2022, The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute, Cell Death Differ., 29, 1071, 10.1038/s41418-022-00976-3 · DOI
  13. Mathe, 2006, Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods, Nucleic Acids Res., 34, 1317, 10.1093/nar/gkj518 · DOI
  14. Ng, 2001, Predicting deleterious amino acid substitutions, Genome Res., 11, 863, 10.1101/gr.176601 · DOI · Paper page
  15. Ben-Cohen, 2022, TP53_PROF: a machine learning model to predict impact of missense mutations in TP53, Brief. Bioinform., 23, 10.1093/bib/bbab524 · DOI
  16. Yamazaki, 2018, Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li-Fraumeni Syndrome Having a Germline TP53 D49H Mutation, J. Pediatr. Hematol. Oncol., 40, e195, 10.1097/MPH.0000000000000948 · DOI
  17. Achatz, 2007, The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families, Cancer Lett., 245, 96, 10.1016/j.canlet.2005.12.039 · DOI
  18. Indeglia, 2023, An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression, Cancer Discov., 13, 1696, 10.1158/2159-8290.CD-22-1315 · DOI
  19. Pinto, 2020, XAF1 as a modifier of p53 function and cancer susceptibility, Sci. Adv., 6, 10.1126/sciadv.aba3231 · DOI
  20. Subasri, 2023, Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome, Cancer Res. Commun., 3, 738, 10.1158/2767-9764.CRC-22-0402 · DOI
  21. Penkert, 2022, Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry, J. Hematol. Oncol., 15, 107, 10.1186/s13045-022-01332-1 · DOI
  22. Landrum, 2016, ClinVar: public archive of interpretations of clinically relevant variants, Nucleic Acids Res., 44, D862, 10.1093/nar/gkv1222 · DOI · Paper page
  23. Tate, 2019, COSMIC: the Catalogue Of Somatic Mutations In Cancer, Nucleic Acids Res., 47, D941, 10.1093/nar/gky1015 · DOI · Paper page
  24. Gudmundsson, 2022, Variant interpretation using population databases: Lessons from gnomAD, Hum. Mutat., 43, 1012, 10.1002/humu.24309 · DOI
  25. Pettersen, 2021, UCSF ChimeraX: Structure visualization for researchers, educators, and developers, Protein Sci., 30, 70, 10.1002/pro.3943 · DOI
  26. Chen, 2010, Crystal Structure of the p53 Core Domain Bound to a Full Consensus Site as a Self-Assembled Tetramer, Structure, 18, 246, 10.1016/j.str.2009.11.011 · DOI
  27. Jeffrey, 1995, Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms, Science, 267, 1498, 10.1126/science.7878469 · DOI

Metadata

Authors
Montellier, E., Lemonnier, N., Penkert, J., Freycon, C., Blanchet, S., Amadou, A., Chuffart, F., Fischer, N. W., Achatz, M.-I., Levine, A. J., Goudie, C., Malkin, D., Bougeard, G., Kratz, C. P., & 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
Elsevier BV
Published
2024-12
Volume
27
Issue
12
Pages
111296
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2024.111296
PMC
PMC11615613
OpenAlex
W4403973465
Cited by
29
References
4
Citations by year
2026: 17 · 2025: 11 · 2024: 1
FWCI
4.97
Type
journal article
Language
en
Open access
Licence
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
  • Child Cancer Aid Trust of German Leukemia Research Support Initiative (DKS2024.03)
  • H2020 Marie Skłodowska-Curie Actions (846806)
  • MSDAVENIR
  • ARC Foundation for Cancer Research
  • Terry Fox Research Institute (1081)
  • University Grenoble Alpes
  • Canadian Imperial Bank of Commerce
  • Bundesministerium für Bildung und Forschung (01GM2205A)
  • Cancéropôle Lyon Auvergne-Rhône-Alpes
  • Horizon 2020 Framework Programme
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review