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 DIVA 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.
Original language | English |
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Pages (from-to) | 1061-1068 |
Number of pages | 7 |
Journal | Oncogene |
Volume | 17 |
Issue number | 9 |
DOIs | |
Publication status | Published - 3 Sept 1998 |
Keywords
- Familial cancer
- Genotype
- Li-Fraumeni syndrome
- Phenotype
- TP53