Mutations and allelic loss of p53 in primary tumor DNA from potentially cured patients with colorectal carcinoma

Purpose: To compare p53 alterations in survivors and nansurvivors after surgery for colorectal cancer. Patients and Methods: Twenty-nine potentially cured patients with colorectal carcinoma, without recurrent disease for more than 6 years after their primary surgery, were selected to match a group of 41 colorectal cancer patients with early metastatic spread to the liver. All patients were screened for mutations in the p53 gene, exons 5 to 9, by denaturing gradient gel electrophoresis and subsequent sequencing. Results: The frequency of p53 mutations was significantly different in cured patients (60%) compared with patients with early relapse (41%, P < .05), A significant difference was found in the distribution of mutations, indicating that potentially cured patients had a different proportion of mutations in conserved regions of p53 (P = .02). this difference wets explained by a significantly different frequency of mutations in exon 8 (40% v 15%, P = .03), which is part of the conserved region V, All mutations in region V were codon 273 mutations in cured patients, whereas three of four mutations were located in codon 273 in patients with metastatic disease. Allelic loss of p53 (loss of heterozygosity [LOH]) was demonstrated in 26% of the cured patients and in 39% of patients with metastatic disease (P = .36), The combination of mutation and LOH of p53 was the same (17%) in both groups. Conclusion: A large number of p53 mutations in colorectal cancer do not promote disease progression. Some mutations, particularly within conserved regions, may even counteract negative functional effects of other p53 structural alterations. A complete loss of p53 function was not related to survival or progression after curative operation of colorectal carcinoma.