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Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome
Abstract
The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.
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“In Li-Fraumeni syndrome (LFS), individuals with TP53 missense mutations show a higher cancer incidence and an earlier age of tumor onset than individuals with truncating or splicing mutations (Birch, et al., 1998).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Birch, et al., 1998
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Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., & Jacks, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.004 · Cited by 1,308
When mutants gain new powers: News from the mutant p53 field
Brosh, R., & Rotter, V. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2693 · Cited by 1,132
Daly, M. B., Pal, T., Berry, M. P., Buys, S. S., Dickson, P., Domchek, S. M., Elkhanany, A. M., Friedman, S., Goggins, M., Hutton, M. L., et al. (2021) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2021.0001 · Cited by 1,143
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TP53 mutations in human cancers: Functional selection and impact on cancer prognosis and outcomes
Petitjean, A., Achatz, M. I. W., Borresen-Dale, A. L., Hainaut, P., & Olivier, M. (2007) · Oncogene · doi:10.1038/sj.onc.1210302 · Cited by 884
Metadata
- Authors
- Birch, J. M., Blair, V., Kelsey, A. M., Evans, D. G., Harris, M., Tricker, K. J., & Varley, J. M.
- Affiliations
- Royal Manchester Children's Hospital (GB)
- Cancer Research UK Manchester Institute (GB)
- Venue
- Oncogene
- Published
- 1998-09-03
- Volume
- 17
- Issue
- 9
- Pages
- 1061-1068
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2051611229
- Cited by
- 200
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 8 · 2013: 8 · 2012: 15
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- Li-Fraumeni syndrome, TP53 mutation, missense mutations, DNA-binding domain, cancer susceptibility, cancer incidence, age at diagnosis, breast cancer, brain tumors, gain-of-function, dominant negative mutation
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, DNA Mutational Analysis, Family, Family Health, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Neoplasms, Pedigree, Phenotype, Cohort Studies, Chi-Square Distribution, Tumor Suppressor Protein p53, Li-Fraumeni Syndrome, Germ-Line Mutation
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