Chromosome 17 Deletions and p53 Gene Mutations in Colorectal Carcinomas

TLDR

Allelic deletions of chromosome 17p occur in over 75 % of colorectal carcinomas and encompass the p53 gene. The authors mapped the common deletion to 17p12–17p13.3 using 20 markers and then sequenced the p53 coding regions in two 17p‑deleted tumors that still expressed p53 mRNA from the remaining allele. Southern/Northern blotting showed no gross p53 alterations, yet sequencing revealed missense mutations at codons 143 and 175 in the remaining allele of two 17p‑deleted tumors, implying that p53 mutations may contribute to colorectal cancer by inactivating its tumor‑suppressor function.

Abstract

Previous studies have demonstrated that allelic deletions of the short arm of chromosome 17 occur in over 75% of colorectal carcinomas. Twenty chromosome 17p markers were used to localize the common region of deletion in these tumors to a region contained within bands 17p12 to 17p13.3. This region contains the gene for the transformation-associated protein p53. Southern and Northern blot hybridization experiments provided no evidence for gross alterations of the p53 gene or surrounding sequences. As a more rigorous test of the possibility that p53 was a target of the deletions, the p53 coding regions from two tumors were analyzed; these two tumors, like most colorectal carcinomas, had allelic deletions of chromosome 17p and expressed considerable amounts of p53 messenger RNA from the remaining allele. The remaining p53 allele was mutated in both tumors, with an alanine substituted for valine at codon 143 of one tumor and a histidine substituted for arginine at codon 175 of the second tumor. Both mutations occurred in a highly conserved region of the p53 gene that was previously found to be mutated in murine p53 oncogenes. The data suggest that p53 gene mutations may be involved in colorectal neoplasia, perhaps through inactivation of a tumor suppressor function of the wild-type p53 gene.