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

Jillian M. Birch, Valerie Blair, Anna M. Kelsey, D. Gareth Evans, Martin Harris, Karen J. Tricker, Jennifer M. Varley

    Research output: Contribution to journalArticlepeer-review


    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 languageEnglish
    Pages (from-to)1061-1068
    Number of pages7
    Issue number9
    Publication statusPublished - 3 Sep 1998


    • Familial cancer
    • Genotype
    • Li-Fraumeni syndrome
    • Phenotype
    • TP53


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