Variation in the human TP53 gene affects old age survival and cancer mortality1
Introduction
Ageing is thought to occur through the accumulation of molecular and cellular damage, which arises because of evolved limitations in mechanisms for maintenance and repair of somatic cells and tissues (Kirkwood, 1996, Kirkwood and Austad, 2000). Survival of most organisms in the natural environment is curtailed by accidental mortality rather than intrinsic deterioration. Under those conditions, there would have been no advantage in investing in higher levels of maintenance than were required to keep the body in good condition for as long as it had a reasonable chance to remain alive. Age-related degenerative processes are seen only at ages that, in the case of humans, were not widely experienced until relatively recently. Accumulated damage causes genomic instability and cellular dysfunction, which in organisms with renewable tissues may result in cancer. The threat posed by genome instability is guarded against by, on the one hand, ‘caretaker’ genes which include genes for DNA repair and are considered longevity assurance genes, and, on the other hand, ‘gatekeeper’ genes which include genes for cell death and cell cycle arrest and are considered tumor suppressor genes (Campisi, 2003). Increased activity of a caretaker gene increases genome stability and both reduces cancer risk and postpones ageing. There is a well documented positive association between longevity and DNA repair capacity (Burkle, 2000, Kirkwood, 1989, Promislow, 1994). However, the relationship between gatekeeper gene functions and the ageing process is more complex since taking a cell permanently out of cycle or deleting it through apoptosis may diminish cancer risk but at the same time accelerate age-related loss in tissue cellularity.
Recent results from mouse models have highlighted the idea that longevity may involve an optimal balance of the tumor-suppressive actions of gatekeeper genes and their pro-ageing effects. In mammals, p53 is the most important gatekeeper gene. A variety of intracellular stress signals activate p53 to induce either transient cell cycle arrest with stimulation of repair activities, senescence or apoptosis (Vogelstein et al., 2000). The nature and intensity of the stress signals, and the cellular context determine which response occurs. P53 deficient (p53−/− and p53+/−) mice are highly susceptible to cancer (Donehower et al., 1992). Interestingly however, two of the p53+/− mice that, presumably by chance, did not develop tumors had unusually long lifespans (Donehower, 2002). On the other hand, mutant p53 (p53+/m) mice that have constitutively activated p53 show greatly reduced cancer incidence but faster ageing; their lifespan is shortened and accompanied by accelerated age-related reduction in mass and cellularity of various tissues (Tyner et al., 2002).
It was shown previously that the two variants of a common codon 72 polymorphism (Arg and Pro) in the human TP53 gene (Harris et al., 1986) differ, most notably in the better ability of the Arg variant to suppress cellular transformation (Thomas et al., 1999) and induce apoptosis (Bonafe et al., 2004, Dumont et al., 2003). Here, we used this tool to test whether tumor suppression in humans has a cost in longevity, firstly by analyzing carriers of the three different TP53 genotypes for cancer risks using a formal meta-analysis of the published literature, and secondly by comparing old-age survival and cancer-mortality in a prospective population-based study of very old people. Indeed we found evidence that a trade-off similar to that seen in mice appears to occur in humans.
Section snippets
Systematic literature review and meta analysis
We searched the National Library of Medicine (PubMed), using the terms p53 AND cancer AND (‘codon 72’ OR ‘cod 72’ OR ‘cod72’ OR ‘position 72’ OR ‘arg’ OR ‘pro’ OR ‘proline’ OR ‘arginine’ OR ‘pro72arg’ OR ‘arg72pro’ OR ‘r72p’ OR ‘p72r’ OR ‘polymorphisms’) The search was limited to human. All abstracts were screened for suitability by two independent researchers. The inclusion criteria were: case-control studies written in English with non-related subjects and sufficient data to calculate odds
Results
We performed a systematic literature review on the association of the TP53 codon 72 polymorphism with cancer susceptibility yielding data from 61 study-populations (Supplementary Table 1 online) for meta-analysis. The conservative estimate using fixed effect pooling was an increase in cancer risk of a factor of 1.11 (1.02–1.22, p<0.05) for TP53 codon 72 Pro/Pro carriers compared to Arg/Arg carriers. Fig. 1 presents a funnel plot with the log odds ratio plotted on the x-axis against the weight
Discussion
The key finding of this study is twofold. First, the data from a systematic literature review showed that the risk to develop cancer was increased for TP53 codon 72 Pro/Pro carriers compared to Arg/Arg carriers. Second, our prospective data show that at age of 85 years and over, the beneficial effects of the TP53 codon 72 Pro/Pro genotype on longevity seem to outweigh its harmful effects on mortality from cancer. In the Italian population, similar Pro allele frequencies were found in three
Acknowledgements
We thank C. de Koning-Treurniet, M. van Schie, and M. van Kersbergen-van Oostrom for technical assistance and T.B. Kirkwood and P. Devilee for critical reading of the manuscript. This work was supported by an IOP (Innovative Oriented Research) grant from the Dutch Ministry of Economic Affairs.
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