TY - JOUR T1 - The <em>p53</em> codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC) JF - Journal of Medical Genetics JO - J Med Genet SP - 769 LP - 773 DO - 10.1136/jmg.2004.028506 VL - 42 IS - 10 AU - S Krüger AU - A Bier AU - C Engel AU - E Mangold AU - C Pagenstecher AU - M von Knebel Doeberitz AU - E Holinski-Feder AU - G Moeslein AU - K Schulmann AU - J Plaschke AU - J Rüschoff AU - H K Schackert Y1 - 2005/10/01 UR - http://jmg.bmj.com/content/42/10/769.abstract N2 - 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. ER -