p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis.

TLDR

Coordinate loss of one p53 allele and mutation of the remaining allele are common in colorectal carcinomas and other cancers. The study aimed to determine how often p53 mutations occur in colorectal tumors that retain both p53 copies and whether such mutations also appear in benign neoplasms. The authors analyzed 58 colorectal tumors, using restriction fragment length polymorphism to detect allelic losses and sequencing of cloned PCR products to identify p53 mutations. p53 mutations were uncommon in adenomas and in tumors retaining both 17p copies, but occurred in 86 % of tumors with a single 17p loss, indicating that point mutation is the rate‑limiting step followed by rapid loss of the remaining allele and that p53 inactivation coincides with the benign‑to‑malignant transition.

Abstract

Coordinate loss of one copy of the p53 gene and mutation of the remaining copy occur in colorectal carcinomas and in many other human malignancies. However, the prevalence of p53 gene mutations in carcinomas which maintain both parental copies of p53 has not previously been evaluated. Moreover, it is not known whether p53 gene mutations are limited to malignant tumors or whether they can also occur in benign neoplasms. To answer these questions, a total of 58 colorectal tumors have been examined; in each tumor, allelic losses were assessed using restriction fragment length polymorphisms and p53 gene mutations were assessed by sequencing cloned polymerase chain reaction products. The following conclusions emerged: (a) p53 gene mutations occurred but were relatively rare in adenomas, regardless of size and whether the adenomas were derived from patients with familial adenomatous polyposis; (b) In carcinomas as well as in adenomas, p53 gene mutations were infrequently observed in tumors which contain both copies of chromosome 17p (17% of 30 tumors), while tumors which lost one copy of chromosome 17p usually had a mutation in the remaining p53 allele (86% of 28 tumors); (c) p53 gene mutations were found at similar frequencies in primary tumor samples and in cell lines derived from tumors. These and other data suggest that the rate limiting step in p53 inactivation is point mutation and that once a mutation occurs, loss of the remaining wild-type allele rapidly follows. Both mutations and allelic losses generally occur near the transition from benign to malignant growth, and the p53 gene may play a causal role in this progression.