ACTIVATION OF THE K-RAS ONCOGENE IN COLORECTAL NEOPLASMS IS ASSOCIATED WITH DECREASED APOPTOSIS

BACKGROUND. Recent in vitro data indicate that the oncogenic effects o f activated ras genes may be mediated, at least in part, through inhib ition of apoptotic cell death. To examine this proposition in vivo, th e relationship between mutations of tile K-ras gene and the frequency of apoptosis nas studied in a series of 69 sporadic colorectal neoplas ms (11 adenomas and 58 carcinomas), METHODS. Mutations in codon 12 of K-ras were determined by a single tube, enriched polymerase chain reac tion, Apoptotic cells in tumor sections were identified by in situ end -labeling of fragmented DNA, whereas levels of bcl-2. and p53 proteins were determined by immunohistochemistry. RESULTS, Tumors with mutant K-ras had a significantly lower apoptotic index than those with the wi ld-type allele (P < 0.05). They were also more likely to exhibit posit ive bcl-2 staining (P < 0.05). Adenomas showed significantly greater b cl-2 positivity than carcinomas (89% and 51%, respectively; P < 0.05). The frequency of apoptosis in these tumors was not related to either bcl-2 positivity or p53 status. CONCLUSIONS. These findings suggest th at activation of K-ras in colorectal carcinoma may inhibit apoptosis a nd thus favor tumor progression. Alternatively, this association may r eflect an accumulation of K-ras mutations in cells in which normal apo ptotic pathways have been impaired. (C) 1997 American Cancer Society.