High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis.

Somatic mutations of the tumor suppressor gene p53 have been frequently detected in esophagal cancers, but their biological significance remains to be established. The tumor suppressor activity of p53 results in part from its ability to transactivate genes involved in the cell cycle and apoptosis, such as p21, bax and PIG3, and some p53 mutations may have a differential effect on the transactivation of these target genes. We developed yeast strains in which the activation by wild-type p53 of reporter plasmids containing p53 binding sites present within these target genes induces a change in the color of the colonies (red/white). Using these strains, we analyzed 56 esophageal cancers from patients residing in Normandy, France, a high incidence geographic area. Forty-seven tumors (84%), scored as mutant with the p21, bax and PIG3 reporter strains and in most of the cases (76%), the percentage of red colonies suggested that both p53 alleles were inactivated. Sequencing analysis allowed the identification of a p53 mutation in each positive sample, and the spectrum of mutations was in agreement with the etiological role of tobacco and alcohol. These results confirm the high frequency of biallelic p53 mutations in esophageal carcinoma and strongly suggest that their biological consequence is the complete alteration of the transactivation of genes involved in the cell cycle and apoptosis, which indicates that p53 alteration is a key event in esophagus carcinogenesis.