Telomerase activation in colorectal carcinogenesis

Telomerase activity has been detected in germ cells as well as in the devel oping embryo. Activity is no longer detectable in most somatic cells of the neonate, although low levels of activity persist in regenerative tissues, Telomerase has been found to be reactivated or up-regulated in the majority of cancers, The colorectal adenoma-carcinoma sequence is one of the best-c haracterized models of multistep tumourigenesis and is thus suitable for de termining at which stage telomerase is activated, Telomerase activity was e xamined by telomeric repeat amplification protocol (TRAP) assay in 96 cases of colorectal tissues, including 50 carcinomas, 31 adenomas, and 15 normal colonic tissues. For each case, histological diagnosis and telomerase acti vity were determined on consecutive frozen sections. In order to reduce the chance of a false-negative TRAP assay due to RNA degradation, the integrit y of rRNA in the tissues was verified in each case. Twenty-five carcinomas, 30 adenomas, and all of the 15 normal colorectal mucosal samples showed no or only partial rRNA degradation and only in these cases was the TRAP assa y interpreted. None of the normal tissues exhibited telomerase activity In contrast, all of the 25 cancers and 47 per cent (14/30) of the adenomas wer e positive. In adenomas, telomerase activation was highly significantly rel ated to the grade of dysplasia (p<0.0001). All adenomas which contained hig h-grade dysplasia revealed telomerase activity, whereas telomerase activity was detectable in only 20 per cent (4/20) of Eases with exclusively low-gr ade dysplasia, These results indicate that telomerase activation, which may be an obligatory step in colorectal carcinogenesis, occurs in the progress ion from low-grade to high-grade dysplasia in adenomas. Furthermore, in the adenoma-carcinoma sequence, telomerase activation seems to occur later tha n K-ras mutation but earlier than p53 mutation. Copyright (C) 1999 John Wil ey & Sons, Ltd.