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

Abstract

To compare p53 alterations in survivors and nonsurvivors after surgery for colorectal cancer. 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. 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 was 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. 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.