Thierry Soussi's Group
Analysis of TP53 mutations heterogeneity in human tumours. The objective of the group is to understand how alterations of the p53 tumour suppressor gene contribute to the heterogeneity of the clinical manifestation of human cancer.
TP53 alterations are the most frequent genetic event in human cancer. In order to have a more accurate picture on the heterogeneity of TP53 loss of function, we have undertake a multidisciplinary program that will combine clinical, in silico and basic analysis to understand how alterations of the p53 tumour suppressor gene contribute to the heterogeneity of the clinical manifestation of human cancer.
For more than 30 years, since my postdoctoral position in 1984, in the laboratory directed by P. May, one of the four discoverers of the TP53 protein, my research has followed a regular course combining both basic research and clinical studies.
Phylogenetic analysis of the TP53 gene (or other genes) can estimate when this gene first appeared, allowing identification of the signalling pathways in which it is involved. Comparison of the sequences of the same gene in different animal species reveals the most highly conserved regions, which generally correspond to domains that are important for the function of the protein.
Analysis of the mutations found in diseases such as cancers can identify variants specifically selected by the pathological process.
Comparison of these two processes in the context of the study of the TP53 gene has been the basis of all of my work since my doctorate thesis: on the one hand phylogeny, a constructive evolutionary process and, on the other hand, neoplastic disease, a destructive process. The TP53 mutation database, developed by my laboratory since 1989, has been an extremely valuable tool in this research, as it constitutes a central link for the analysis of these two processes and raises numerous working hypotheses that have driven my research over the years.
- What is the function of the most phylogenetically conserved residues?
- What p53 functions are inactivated in the most frequently mutated mutants (hot spot regions)?
- What p53 functions are associated with phylogenetically conserved p53 residues that are never mutated in cancers (cold spot regions)?
- What is the clinical value of TP53 mutations in human cancer and how can they be diagnosed?
Reporting, storing, classifying and analysing these mutations constitute a major challenge (Horaitis and Cotton, 2004). For a long time, locus-specific databases (LSDB) have been developed for this purpose. Most of them are a list of mutations collected in publications and no information indicating whether or not these are passenger or driver mutations are available. TP53 mutation (TP53; MIM# 191170) database is a paradigm, as it constitutes the largest collection of somatic mutations for a single gene.
The UMD TP53 database is one of the oldest TP53 mutation databases. Created in 1989 by my group, it has been regularly updated and the most recent version, released in January 2017, includes more than 80,000 TP53 mutations and it is the most up-to-date TP53 collection currently available (Caron de Fromentel and Soussi, 1992; Soussi and Beroud, 2001; Soussi et al., 2006; Soussi, 2014). This database includes key information that is not available in other large repositories, such as TCGA, COSMIC or ICIG. Furthermore, compared to these large repositories, the UMD TP53 database does not comprise any specific bias with respect to particular TP53 variants (Soussi et al., 2017).
Accurate assessment of TP53 gene status in sporadic tumours and in the germline of individuals at high risk of cancer, such as Li-Fraumeni Syndrome (LFS), has important clinical implications for diagnosis, surveillance and therapy and has now reached a clinical practice phase. In this context, we have recently reported recommendations and guidelines for the analysis of TP53 gene alterations in routine clinical practice (Leroy et al., 2017). This paper is freely available here.
Analysis of TP53 mutation status in human cancer cell lines: a reassessment.
Hum. Mutat. 2014 Jun;35(6):756-65