Focus on the p53 gene and cancer: Advances in TP53 mutation research

The year 1989 was critical for the p53 gene (TP53), with the publication of the first mutations and its entry into the world of tumor suppressor genes [Baker et al., 1989; Takahashi et al., 1989]. The p53 gene went from being a gene which everyone strongly recommended to avoid studying because it was considered to be uninteresting and non-innovative to a star gene. It reached a highpoint in 1993 when it was called ‘‘molecule of the year’’ by the journal Science [Harris, 1993; Lane and Benchimol, 1990]. From a more personal point of view, I decided to work on p53 in 1984, following my appointment as Assistant Professor. With a teaching workload of 190 hours per year, I had to select a research topic which was not going to be a subject of frantic international competition. I still ask myself whether I made the right choice! This 1989 transition which, retrospectively, could have been anticipated, opened up a new era in which thousands of people became involved and in which tens of millions of dollars were invested. Was it worth all this effort? Have the thousands of published studies devoted to definition of p53 gene status–in order to more clearly define clinical aspects such as response to treatment or prognosis–actually improved patient management? The objective of this special issue of Human Mutation is not to provide a definitive answer to these questions. If only one lesson can be drawn from the history of studies of the p53 gene, as well as other genes, it is that all conclusions are only contextual and circumstantial, and never definitive and absolute. Nevertheless, almost 15 years after identification of the first p53 mutations, it is now possible to present a review of various aspects of these studies. An unexpected, but very informative, aspect is the discovery of the relationship between the nature of mutational events leading to alteration of the p53 gene and the deliberate or accidental exposure of patients to carcinogens. In 1991–1992, the first compilations of p53 gene mutations demonstrated the specificity of G-T transversions that were specifically detected in smoking-related cancers [Caron de Fromentel and Soussi, 1992; Hollstein et al., 1991]. Since this observation, many studies have analyzed this molecular archaeology and have demonstrated significant correlations between gene p53 mutations and exposure to various types of carcinogens. These studies have also led to the creation of gene p53 mutation databases which are accessible to the entire scientific community [Soussi et al., 2000; Hainaut and Hollstein, 2000; Olivier et al., 2002]. The clinical significance of p53 gene mutations has been the subject of a number of controversies, a fairly common situation for this type of study. The situation concerning p53 has been exacerbated by the marked diversity of methodological approaches. One of the major difficulties concerns comparison of immunohistochemical analyses that are used to evaluate accumulation of stable p53 mutations in tumor cells and molecular analyses that demonstrate the nature of the mutational events that inactivated the p53 gene. It has now been clearly established that the concordance between these two approaches is only 70%, with a marked heterogeneity between the various types of cancers [Soussi and Béroud, 2001]. The frequency of nonsense or frameshift mutations not leading to the synthesis of mutant p53 protein is heterogeneous from one type of cancer to another and may also present geographical variations related to exposure to different carcinogens. TP53 mutations now also appear to be heterogeneous not only in terms of loss of function, but also in terms of a possible gain