The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC)

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • S. Krüger - , Abteilung Chirurgische Forschung (Autor:in)
  • A. Bier - , Institut für Klinische Genetik (Autor:in)
  • C. Engel - , Universität Leipzig (Autor:in)
  • E. Mangold - , Universität Bonn (Autor:in)
  • C. Pagenstecher - , Universität Bonn (Autor:in)
  • M. Von Knebel Doeberitz - , Universität Heidelberg (Autor:in)
  • E. Holinski-Feder - , Ludwig-Maximilians-Universität München (LMU) (Autor:in)
  • G. Moeslein - , Heinrich Heine Universität Düsseldorf (Autor:in)
  • K. Schulmann - , Ruhr-Universität Bochum (Autor:in)
  • J. Plaschke - , Abteilung Chirurgische Forschung (Autor:in)
  • J. Rüschoff - , Klinikum Kassel GmbH (Autor:in)
  • H. K. Schackert - , Abteilung Chirurgische Forschung (Autor:in)

Abstract

The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the praline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/ pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.

Details

OriginalspracheEnglisch
Seiten (von - bis)769-773
Seitenumfang5
FachzeitschriftJournal of medical genetics
Jahrgang42
Ausgabenummer10
PublikationsstatusVeröffentlicht - Okt. 2005
Peer-Review-StatusJa

Externe IDs

PubMed 16199549

Schlagworte

Ziele für nachhaltige Entwicklung

ASJC Scopus Sachgebiete