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Cited by 200Cancer-related Molecular PathwaysGenetic factors in colorectal cancerBRCA gene mutations in cancer

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome

Birch, Jillian M, Blair, Valerie, Kelsey, Anna M, Evans, D Gareth, Harris, Martin, Tricker, Karen J, Varley, Jennifer M·1998·Oncogene
DOI 10.1038/sj.onc.1202033
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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, people with TP53 missense mutations have higher cancer incidence and earlier tumor onset than people with truncating or splicing mutations.

    “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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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)
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
1998-09-03
Volume
17
Issue
9
Pages
1061-1068
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/sj.onc.1202033
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
Licence
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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