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Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1?
  1. A-M Martin1,2,3,
  2. P A Kanetsky4,5,
  3. B Amirimani2,
  4. T A Colligon2,3,
  5. G Athanasiadis2,3,
  6. H A Shih2,
  7. M R Gerrero2,3,
  8. K Calzone3,
  9. T R Rebbeck4,5,
  10. B L Weber2,3
  1. 1Laboratory of Molecular Pathology, Department of Pathology, Pennsylvania Hospital, Philadelphia, USA
  2. 2Department of Medicine, University of Pennsylvania, Philadelphia, USA
  3. 3Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, USA
  4. 4Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, USA
  5. 5Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA
  1. Correspondence to:
 Dr B L Weber, Room 514, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; 
 weberb{at}mail.med.upenn.edu

https://doi.org/10.1136/jmg.40.4.e34

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    Somatic mutations in TP53 are the most frequent events in human cancer and lead to inactivation of the gene, loss of tumour suppressor function, and in some cases generation of a dominant negative form of p53.1–3 Eleven exons make up the primary transcript of TP53, of which exons 2–11 encode the protein. Five conserved domains exist in exons 1, 4, 5, 7, and 8,4 which are considered essential for normal p53 function. Approximately 90% of disease associated mutations occur in these domains, with mutations in five codons (175, 245, 248, 249, and 273) accounting for approximately 20% of all mutations reported to date.

    Germline mutations in TP53 cause Li-Fraumeni syndrome (LFS), a familial association of childhood leukaemia, brain cancer, soft tissue sarcoma, and adrenal cortical carcinoma,5,6 as well as other cancers such as breast cancer, melanoma, germ cell tumours, and carcinomas of the lung, pancreas, and prostate.7,8 Cancers characteristically develop at unusually early ages and multiple primary tumours are frequent. Susceptibility to cancer in these families follows an autosomal dominant pattern of inheritance7 and among families with a known germline TP53 mutation the probability of developing any invasive cancer (excluding carcinomas of the skin) approaches 50% by the age of 30, compared to an age adjusted population incidence of cancer of 1%. It is estimated that more than 90% of TP53 mutation carriers will develop cancer by the age of 70.9

    In addition to the numerous mutations, TP53 also contains several polymorphisms that may alter its activity. In particular, at nucleotide 215 (codon 72) there is a single base pair variant (g.215G>C) in the coding region, which results in a substitution of proline for arginine in the protein sequence.10 The frequency of this polymorphism varies from 26–35%11–13 …

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