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 det ected 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, s uch as p21, bar and PIG3, and some p53 mutations may have a differential ef fect on the transactivation of these target genes. We developed yeast strai ns in which the activation by wild-type p53 of reporter plasmids containing p53 binding sites present within these target genes induces a change in th e color of the colonies (red/ white). Using these strains, we analyzed 56 e sophageal cancers from patients residing in Normandy, France, a high incide nce geographic area, Forty-seven tumors (84%), scored as mutant with the p2 1, bar and PIG3 reporter strains and in most of the cases (76%), the percen tage of red colonies suggested that both p53 alleles were inactivated. Sequ encing analysis allowed the identification of a p53 mutation in each positi ve sample, and the spectrum of mutations was in agreement with the etiologi cal role of tobacco and alcohol. These results confirm the high frequency o f biallelic p53 mutations in esophageal carcinoma and strongly suggest that their biological consequence is the complete alteration of the transactiva tion of genes involved in the cell cycle and apoptosis, which indicates tha t p53 alteration is a key event in esophagus carcinogenesis.