Variation in the human TP53 gene affects old age survival and cancer mortality.
Longevity may depend on a balance between tumor suppression and tissue renewal mechanisms [Campisi, J., 2003. Cancer and ageing: rival demons? Nat. Rev. Cancer 3 (5), 339-349]. Mice with constitutively activated p53 are almost cancer free but their life span is reduced and accompanied by early tissue atrophy [Tyner et al., 2002. p53 mutant mice that display early ageing-associated phenotypes. Nature 415 (6867) 45-53]. Replacement of arginine (Arg) by proline (Pro) at position 72 of human p53 decreases its apoptotic potential [Dumont et al., 2003. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet. 33 (3), 357-365] providing a tool to test for a similar trade-off in humans. Using a formal meta-analysis of the published literature we show that carriers of the TP53 codon 72 Pro/Pro genotype have an increased cancer risk compared to Arg/Arg carriers (p<0.05). Next, in a prospective study of 1226 people aged 85 years and over we show that carriers of the Pro/Pro genotype have a 41% increased survival (p = 0.032) despite a 2.54 fold increased (p = 0.007) proportional mortality from cancer. It is suggested that human p53 protect against cancer but at a cost of longevity.
van Heemst
Diana
D
Mooijaart
Simon P
SP
Beekman
Marian
M
Schreuder
Jeroen
J
de Craen
Anton J M
AJ
Brandt
Bernd W
BW
Slagboom
P Eline
PE
Westendorp
Rudi G J
RG
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008136:Longevity / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D011110:Polymorphism, Genetic