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The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC)
  1. S Krüger1,
  2. A Bier2,
  3. C Engel3,
  4. E Mangold4,
  5. C Pagenstecher4,
  6. M von Knebel Doeberitz5,
  7. E Holinski-Feder6,
  8. G Moeslein7,
  9. K Schulmann8,
  10. J Plaschke1,
  11. J Rüschoff9,
  12. H K Schackert1,
  13. the German HNPCC Consortium
  1. 1Department of Surgical Research, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden, Germany
  2. 2Institute of Clinical Genetics, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden, Germany
  3. 3Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Liebigstrasse 27, D-04103 Leipzig, Germany
  4. 4Institute of Human Genetics, University Hospital Bonn, Wilhelmstraße 31, D-53111 Bonn, Germany
  5. 5Institute of Molecular Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany
  6. 6Department of Medical Genetics, University of Munich, Goethestrasse 29, D-80336 Munich, Germany
  7. 7Department of Surgery, Heinrich-Heine-University Duesseldorf, Moorenstraße 5, D-40225 Duesseldorf, Germany
  8. 8Ruhr University Bochum, Medical Department, Knappschaftskrankenhaus, In der Schornau 23-25, D-44892 Bochum, Germany
  9. 9Institute of Pathology, Klinikum Kassel, Moenchebergstrasse 41-43, D-34125 Kassel, Germany
  1. Correspondence to:
 Dr S Krüger
 Department of Surgical Research, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden, Germany; e-mail:


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 proline (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.

  • p53 codon 72
  • hereditary non-polyposis colorectal cancer (HNPCC)
  • mismatch repair (MMR) system
  • age of onset (AO)

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  • Competing interests: none declared