TP53 is often inactivated by missense mutations, in contrast to many other tumor suppressors such as APC, RBI, BRCA1 or p16/ CDKN2A that are commonly inactivated by deletion or nonsense mutations (Olivier et al., 2004). Of the 20 000 mutations reported to date, about 75% are singlebase substitutions and most of them occur within exons encoding the DNA-binding domain (IARC TP53 mutation database, www-p53.iarc.fr). Most of these mutations impair DNA-binding by disrupting the architecture of this domain or by eliminating contact points between the protein and target DNA (Cho et al., 1994). About 30% of missense mutations affect six "hotspot" codons (175, 245, 248, 249, 273 and 282) (Figure 16.1). The other mutations are scattered over 200 different codons. Mutations occur through a number of biochemical pathways, including ''induced'' ones (that is, resulting from the direct attack of carcinogens at specific bases in the TP53 sequence) and ''spontaneous'' ones (resulting from endogenous DNA modifications, imperfect DNA repair or polymerase errors during replication). Reading and interpreting mutation patterns in TP53 to find out ''carcinogen fingerprints" has become a favourite sport for many TP53 mutation screeners (Hainaut and Hollstein, 2000; Olivier et al., 2004).
There is no basis to the view that TP53 lies in a "hypermutable" region of the genome. Thus, the high frequency and distribution of mutations reflects the acquisition of a selective advantage for tumorigenesis induced by the mutation. Indeed, inactivation of p53 function deletes a major cancer protection system by allowing cells with damaged DNA to replicate. Two main selection mechanisms can be proposed. The first accounts for the high rate of TP53 mutations in tumors arising from intense exposure to environmental carcinogens such as, for example, lung cancer in smokers. In normal lung cells of heavy smokers, the high load of DNA damage over long periods of time generates a global suppression of cell growth, only compensated by the capacity of the cells to keep p53 function under control. When tobacco carcinogens hit within the TP53 sequence to induce an inactivating mutation, the cell that has acquired such a mutation escapes stress-induced suppression and thus immediately gains a growth advantage against neighboring normal cells. This mechanism explains why the prevalence of TP53 mutations in lung cancers of smokers shows a strict dose-dependence with tobacco consumption (Hainaut and Hallstein, 2000; Pfeifer et al., 2002). In this model of carcinogenesis, TP53 mutation is a very early, if not the earliest genetic modification that arises on the path to cancer. Indeed, high-sensitivity assays have shown that mutant TP53 is detectable in non-cancer normal tissues of individuals exposed to exogenous or endogenous carcinogens (Hussain etal., 2000; 2001).
The second selection mechanism acts through the p14Arf-Mdm-2 connection. Through this connection, excessive activation of growth factor signalling (e.g through mutation of RAS genes, or constitutive activation of growth factor receptors) triggers p53 activation and growth suppression. In parallel with this mechanism, even limited hyperplasia in a solid tissue may lead to hypoxia and induction of p53 through yet another pathway
(Bardos and Ashcroft, 2004). Thus, only cells that contain a pre-existing TP53 mutation will escape this control and will be allowed to proliferate under such critical conditions. In this context, a TP53 mutation may appear, clinically, as a ''late'' event, and will be detectable only in lesions that have reached a certain stage in their progression. This is apparently the case for colorectal cancer developing according to a polyp-adenoma-carcinoma sequence, where TP53 mutations become highly prevalent at the adenoma-carcinoma transition. It should be kept in mind, however, that the mutation may have occurred well ahead of this pathological transition, and becomes detectable in the lesion as a consequence of the expansion of a biologically selected clone. The selective advantage may result from enhanced survival in the poor physiological conditions which cancer cells are faced with during invasion (Guimaraes and Hainaut, 2002).
Was this article helpful?
Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.