Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors
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We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.
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The relative increase in childhood ACC incidence is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in ∼50% to 80% of children with ACC.
“The relative increase in incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in ∼50% to 80% of children with ACC (Table 1)(28–30).”
From Adrenocortical carcinoma (2014) · cites this paper as [29]
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- Authors
- Varley, J. M., McGown, G., Thorncroft, M., James, L. A., Margison, G. P., Forster, G., Evans, D. G. R., Harris, M., Kelsey, A. M., & Birch, J. M.
- Affiliations
- Cancer Research UK Manchester Institute (GB)
- St Mary's Hospital (GB)
- The Christie Hospital (GB)
- Royal Manchester Children's Hospital (GB)
- Corresponding author
- Varley, Jennifer M.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 65
- Issue
- 4
- Pages
- 995-1006
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1288270
- OpenAlex
- W2039634774
- Cited by
- 266
- References
- 63
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 9 · 2019: 8 · 2018: 6 · 2017: 12 · 2016: 8 · 2015: 11 · 2014: 9 · 2013: 14 · 2012: 16
- FWCI
- 10.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- TP53, germline TP53 mutation, low penetrance, loss of heterozygosity, Li-Fraumeni syndrome, cancer susceptibility, genetic testing
- MeSH terms
- MutL Protein Homolog 1, Adolescent, Adrenal Cortex Neoplasms, Adult, Aged, Alleles, Carrier Proteins, Child, Child, Preschool, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Testing, Humans, Immunohistochemistry, Male, Middle Aged, Molecular Sequence Data, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Genes, p53, Li-Fraumeni Syndrome, Age of Onset, Germ-Line Mutation, Polymorphism, Single-Stranded Conformational, Microsatellite Repeats, Loss of Heterozygosity, Penetrance, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, MutS Homolog 2 Protein
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