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Mutant p53 and MDM2 in Cancer pp 1–16Cite as

p53 and Hereditary Cancer

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Part of the book series: Subcellular Biochemistry ((SCBI,volume 85))

Abstract

The roles of p53 as “guardian of the genome” are extensive, encompassing regulation of the cell cycle, DNA repair, apoptosis, cellular metabolism, and senescence - ultimately steering cells through a balance of death and proliferation. The majority of sporadic cancers exhibit loss of p53 activity due to mutations or deletions of TP53, and alterations in its signaling pathway. Germline TP53 mutations have been identified in a group of families exhibiting a rare but highly penetrant familial cancer syndrome, called the Li-Fraumeni syndrome (LFS). Between 60–80% of ‘classic’ LFS families carry mutant Trp53. The most frequent cancers observed are premenopausal breast cancer, bone and soft-tissue sarcomas, adrenal cortical carcinomas, and brain tumors. Penetrance is nearly 100% by age 70. Although TP53 is currently the only validated susceptibility locus recognized for LFS, recent studies have focused on the identification of genetic modifiers that may explain the wide phenotypic variability observed in LFS patients. Analyses of single nucleotide polymorphisms (SNPs), genome-wide copy number and telomere length have provided greater insight into the potential genetic modifiers of LFS. Moreover, the study of Trp53 mutant heterozygous mouse models has elucidated novel functions of p53, and offers insight into the mechanisms governing tumorigenesis in LFS. The key findings outlined in this chapter provide an overview of the molecular basis of LFS and the role of p53 in this unique heritable cancer syndrome.

This work is supported in part by a grant from the Canadian Institutes of Health Research (DM). Ms. Merino is supported in part by a Vanier Scholarship of the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Avenue, M5G 1X8, Toronto, ON, Canada

    Diana Merino M.Sc. & David Malkin M.D.

  2. Departments of Pediatrics and Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Diana Merino M.Sc. & David Malkin M.D.

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  1. Diana Merino M.Sc.
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  2. David Malkin M.D.
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Correspondence to David Malkin M.D. .

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Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Swati Palit Deb

  2. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Sumitra Deb

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Merino, D., Malkin, D. (2014). p53 and Hereditary Cancer. In: Deb, S., Deb, S. (eds) Mutant p53 and MDM2 in Cancer. Subcellular Biochemistry, vol 85. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9211-0_1

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