Variation in the human TP53 gene affects old age survival and cancer mortality

Diana Van Heemst, Simon P. Mooijaart, Marian Beekman, Jeroen Schreuder, Anton J.M. De Craen, Bernd W. Brandt, P. Eline Slagboom, Rudi G.J. Westendorp

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174 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)11-15
Number of pages5
JournalExperimental Gerontology
Volume40
Issue number1-2
DOIs
StatePublished - Jan 2005
Externally publishedYes

Keywords

  • Cancer
  • Codon 72
  • Old age survival
  • TP53
  • Tissue renewal

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