The Inherited p53 Mutation in the Brazilian Population

Abstract

A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ∼15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ∼100 million. Moreover, it has been determined that carriers of this founder mutation display variable tumor susceptibility, ranging from isolated cases of pediatric ACC to Li-Fraumeni or Li-Fraumeni-like (LFL) syndromes, thus representing a significant medical issue for this country. Studying the biochemical and molecular consequences of this mutation on p53 tumor-suppressor activity, as well as the putative additional genetic alterations that cooperate with this mutation, is advancing our understanding of how p53 functions in tumor suppression in general. These studies, which originated with a rare childhood tumor, are providing important information for guiding genetic counselors and physicians in treating their patients and are already providing clinical benefit.

Figure 1.

p53 structural domains and germline mutations associated with human cancers. Structural domains of p53 protein are schematically diagrammed. Cancer associated mutations (including the classical hotspot mutations) are identified according to the frequency and position within TP53. Note the high frequency of the constitutional p.R337H mutation common in Southern Brazil (see the International Agency for Research on Cancer [IARC] TP53 database, p53.iarc.fr) (Petitjean et al. 2007).

Figure 2.

The p53 tetramerization domain. The stabilizing salt bridges involving Arg 337 and Asp 352 within the dimer (left) and tetramer (right) complexes are highlighted. (From DiGiammarino et al. 2002; reprinted, with permission, from the authors and Nature Publishing Group © 2002.)

Figure 3.

Pedigrees of high-risk Brazilian family associated with germline TP53-R337H mutation.