Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers
Abstract
Purpose: The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods: From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results: The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.
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Four cases in the complex rearrangement subgroup had germline pathogenic variants in ATM, CHEK2, or TP53, all with somatic LOH.
“Four cases within this group harboured germline pathogenic variants in ATM [23], CHEK2 [24] or TP53 [25], all with somatic LOH.”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [25]
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- Authors
- Bougeard, G., Renaux-Petel, M., Flaman, J.-M., Charbonnier, C., Fermey, P., Belotti, M., Gauthier-Villars, M., Stoppa-Lyonnet, D., Consolino, E., Brugières, L., Caron, O., Benusiglio, P. R., Bressac-de Paillerets, B., Bonadona, V., Bonaïti-Pellié, C., Tinat, J., Baert-Desurmont, S., & Frebourg, T.
- Affiliations
- Inserm (FR)
- Gaëlle Bougeard, Mariette Renaux-Petel, Jean-Michel Flaman, Camille Charbonnier, Pierre Fermey, Julie Tinat, Stéphanie Baert-Desurmont, Thierry Frebourg, Institut National de la Santé et de la Recherche Médicale (Inserm) U1079, University of Rouen, Institute for Research and Innovation in Biomedicine; Julie Tinat, Stéphanie Baert-Desurmont, Thierry Frebourg, University Hospital, Rouen; Muriel Belotti, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Curie Institute, Paris; Emilie Consolino, Laurence...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-07-20
- Volume
- 33
- Issue
- 21
- Pages
- 2345-2352
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2095770043
- Cited by
- 760
- References
- 42
- Citations by year
- 2026: 68 · 2025: 85 · 2024: 95 · 2023: 67 · 2022: 82 · 2021: 81 · 2020: 78 · 2019: 59 · 2018: 42 · 2017: 64 · 2016: 30 · 2015: 9
- FWCI
- 21.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- Li-Fraumeni syndrome, germline TP53 mutation, cancer susceptibility, multiple primary neoplasms, childhood tumors, osteosarcoma, adrenocortical carcinoma, choroid plexus carcinoma, breast cancer, soft tissue sarcoma, central nervous system tumors, loss-of-function mutations, genome rearrangement, mutation classification
- MeSH terms
- Adolescent, Adult, Female, France, Genetic Testing, Genotype, Humans, Male, Phenotype, Tumor Suppressor Protein p53, Li-Fraumeni Syndrome, Sequence Analysis, DNA, Age of Onset, Germ-Line Mutation
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