Investigations on a clinically and functionally unusual and novel germline p53 mutation.
Bottom Line: Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual.These results led us to carry out more detailed functional tests on the mutant protein.However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.
Affiliation: Richard Dimbleby Department Cancer Research, Guy's, King's and St Thomas' School of Medicine, St Thomas' Hospital, London SE1 7EH, UK.Show MeSH
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Mentions: The tumour suppressor gene p53 was discovered in 1979 because of its ability to bind to large T antigen (Lane and Crawford, 1979). p53 is a nuclear phosphoprotein that plays a central role in the cellular response to DNA damage by inducing either G1 arrest or apoptosis. It functions mainly through its ability to transactivate or repress target genes. Inactivation of wild-type p53 by mutation or interaction with cellular or viral proteins has been found to occur in over 50% of human cancers (Levine, 1997). Li-Fraumeni Syndrome (LFS), which is a rare dominantly inherited cancer predisposition syndrome, is associated with germline p53 mutations (Malkin et al, 1990). Individuals with LFS are at increased risk of developing a large spectrum of cancers, often with a very early onset and multiple primary tumours are common. Primary choroid plexus tumours are rare and usually occur in early childhood. However, several families with LFS have been described, in which there are individuals with choroid plexus tumours, sometimes in young adults (Garber et al, 1990). There have been four reports of germline p53 mutations in families with LFS and childhood choroid plexus tumours (Frebourg et al, 1995; Jolly et al, 1994; Sedlacek et al, 1998; Vital et al, 1998). In this report we describe an adult patient with a novel germline 7 base pair insertion in the p53 gene who presented with an osteosarcoma of the femur at the age of 22 years. This tumour was treated successfully by surgery and chemotherapy. At 29 years, she presented with a choroid plexus tumour which was shown on histology to be an atypical choroid plexus papilloma. There was no unusual family history of cancer (Figure 1Figure 1
Affiliation: Richard Dimbleby Department Cancer Research, Guy's, King's and St Thomas' School of Medicine, St Thomas' Hospital, London SE1 7EH, UK.