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 sur gery for colorectal cancer. Patients and Methods: Twenty-nine potentially cured patients with colorecta l carcinoma, without recurrent disease for more than 6 years after their pr imary surgery, were selected to match a group of 41 colorectal cancer patie nts with early metastatic spread to the liver. All patients were screened f or mutations in the p53 gene, exons 5 to 9, by denaturing gradient gel elec trophoresis and subsequent sequencing. Results: The frequency of p53 mutations was significantly different in cure d patients (60%) compared with patients with early relapse (41%, P < .05), A significant difference was found in the distribution of mutations, indica ting that potentially cured patients had a different proportion of mutation s 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 we re codon 273 mutations in cured patients, whereas three of four mutations w ere 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 comb ination 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 pro mote disease progression. Some mutations, particularly within conserved reg ions, may even counteract negative functional effects of other p53 structur al alterations. A complete loss of p53 function was not related to survival or progression after curative operation of colorectal carcinoma.