Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
AuthorsBirch, Jillian M
Kelsey, Anna M
Evans, D Gareth R
Tricker, K J
AffiliationCRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK.
MetadataShow full item record
AbstractThe 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.
CitationCancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. 1998, 17 (9):1061-8 Oncogene
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