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Genetic Counseling for TP53 Germline Mutations

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p53 in the Clinics

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Abstract

Li–Fraumeni syndrome (LFS; OMIM # 151623) is an autosomal dominant disorder associated with multiple early-onset cancers. Classic LFS and its variants, collectively named Li–Fraumeni-like (LFL) syndrome, are two recognized forms of the syndrome. It is estimated that carriers of a germlineTP53 mutation have, on average, a 50 % risk to develop cancer before the age of 40 years and a life risk of 90 %. Clinical management of individuals with LFS/LFL is a major challenge due to the wide tumor spectrum. Monitoring strategies have shown to reduce mortality in carriers of TP53 germline mutations. Cancer-prone families of Southeastern Brazil have been identified to carry a founder germline TP53 mutation (c.1010G>A, p.R337H) at an unusually high prevalence of about 1:300 subjects (0.3 %). Structural and functional studies have identified that p.R337H mutant proteins have an in vitro pH-dependent defect in the oligomerization domain, making them inactive only in conditions of increased intracellular pH. The TP53 p.R337H allele is a unique example of a pathogenic founder mutation persisting among a large and mixed population. Genetic counseling should integrate the clinical assessment and care of all individuals carrying TP53 germline mutations. The complexity of the diagnosis and prognostic definitions, as well as the long-term impact of being diagnosed with a germline TP53 mutation on mutation carriers and their relatives, calls for a multidisciplinary approach to counseling, involving health care professionals from multiple areas of expertise.

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Authors and Affiliations

  1. Department of Oncogenetics, Oncogenomics Program, Hospital A.C. Camargo – Fundação Antônio Prudente, Rua Professor Antonio Prudente, 211 – 1oSS, CEP 01509-010, São Paulo, SP, Brazil

    Maria Isabel Waddington Achatz M.D., Ph.D.

  2. Departamento de Genética, UFRGS e SGM-HCPA, Rua Ramiro Barcelos 2350, Porto Alegre, RS, 90035-903, Brazil

    Patricia Ashton-Prolla M.D., Ph.D.

  3. Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, RS, 90035-903, Brazil

    Patricia Ashton-Prolla M.D., Ph.D.

Authors
  1. Maria Isabel Waddington Achatz M.D., Ph.D.
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  2. Patricia Ashton-Prolla M.D., Ph.D.
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Corresponding author

Correspondence to Maria Isabel Waddington Achatz M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. International Prevention Research Instit, 95 cours Lafayette, Lyon, 69006, France

    Pierre Hainaut

  2. International Agency for Cancer Research, 150 Cours Albert-Thomas, Lyon, 69372, France

    Magali Olivier

  3. Cancer Center Karolinska (CCK), Dept. Oncology and Pathology, Karolinska Institute, Karolinska Institutet, Stockholm, 171 76, Sweden

    Klas G. Wiman

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© 2013 Springer Science+Business Media New York

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Achatz, M.I.W., Ashton-Prolla, P. (2013). Genetic Counseling for TP53 Germline Mutations. In: Hainaut, P., Olivier, M., Wiman, K. (eds) p53 in the Clinics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3676-8_18

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