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Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

Oncogene volume 19, pages 4230–4235 (2000)Cite this article

Abstract

Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with Li-Fraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-specific DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations affected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9. These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families.

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Acknowledgements

We thank Dr Christine Li for technical assistance, Dr Lisa DiGianni for family pedigree analyses, Anastasia Satterfield for sample and data tracking, Katherine Schneider for family counseling, and Dr Judy Garber for helpful comments with manuscript preparation. The work was supported by The Starr Foundation and by a Skin Disease Research Center grant from NIAMS. Dr FP Li is a Harry and Elsa Jiler American Cancer Society Clinical Research Professor.

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Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, MA, USA

    Sigitas J Verselis

  2. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, MA, USA

    Frederick P Li

  3. Department of Medicine and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    James G Rheinwald

  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, MD, USA

    Joseph F Fraumeni Jr

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Verselis, S., Rheinwald, J., Fraumeni, J. et al. Novel p53 splice site mutations in three families with Li-Fraumeni syndrome. Oncogene 19, 4230–4235 (2000). https://doi.org/10.1038/sj.onc.1203758

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