What 20 years of research has taught us about the TP53 p.R337H mutation

Abstract

The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families.

Keywords: TP53; R337H; cancer predisposition; founder mutation; haplotype.

Figure 1

Structure of p53. (Top) Schematic view of the domain structure of p53. The columns indicate the relative frequency of cancer‐associated mutations for each residue according to the International Agency for Research on Cancer database. For instance, p.R337H is the variant most commonly reported and seen in patients from Brazil and other countries. (Bottom) The 393‐residue p53 protein comprises an N‐terminal transactivation domain (yellow), which is followed by a proline‐rich region (brown), a central DNA‐binding core domain (blue), a tetramerization domain (green), and a negative regulatory domain (light blue) at the extreme C‐terminus. Positions of polymorphic markers and single‐nucleotide polymorphisms that define the p.R337H founder allele are indicated. UTR indicates untranslated region; VNTR, variable number tandem repeat.

Figure 2

Schematic diagram of TP53 p.R337H haplotypes. Red bars represent the constitutive haplotypes observed in p.R337H carriers. All carriers of p.R337H share a common TP53 sequence (short red bar). However, the most commonly observed haplotype encompasses a region of 2 cM and harbors mutations in TP53 and XAF1 (long red bar).