K-RAS AND P53 ALTERATIONS IN GENOMIC DNA AND TRANSCRIPTS OF HUMAN PANCREATIC ADENOCARCINOMA CELL-LINES

We analyzed 15 human pancreatic adenocarcinoma cell lines for alterati ons of the K-ras and the p53 genes and their transcripts. In 11 cell l ines (73.3%), point mutations of the K-ras gene were found at codon 12 in exon 1. In 9 cell lines one allele was mutated and the other was w ild type, and both the alleles were expressed into mRNA. In one cell l ine both alleles of codon 12 were mutated to TGT and GTT, respectively , but only TGT was transcribed into mRNA. Alterations in mRNA of the p 53 gene were detected in 10 cell lines (66.7%). Analysis of the genomi c sequence of the p53 gene revealed that the alterations consisted of 6 cases of base pair substitutions and 1 case of 1-bp deletion in evol utionarily conserved exons 5 to 8, 2 cases of splicing mutations in ex on 4, and 1 case of novel deletion from exons 2 to 9. In 14 cell lines (93.3%), alterations were identified in the K-ras or p53 gene. Of the se, 4 cell lines harbored K-ras mutations without p53 alteration, wher eas 3 cell lines exhibited p53 alterations without K-ras mutation. Thu s, it is suggested that activation of the K-ras gene and inactivation of the p53 gene are strongly and cooperatively associated with pancrea tic carcinogenesis.