DNA METHYLATION OF THE PEPSINOGEN-1 GENE DURING RAT GLANDULAR STOMACHCARCINOGENESIS INDUCED BY N-METHYL-N'-NITRO-N-NITROSOGUANIDINE OR CATECHOL

The methylation patterns of the rat pepsinogen 1 (Pg1) gene in preneop lastic and neoplastic stomach lesions induced by genotoxic N-methyl-N' -nitro-N-nitrosoguanidine (MNNG) or the non-genotoxic carcinogen catec hol were investigated. Male WKY/Ncrj rats were given MNNG in their dri nking water (50 mg/1) for 30 weeks or 0.8% catechol throughout the exp eriment (60 weeks). MNNG induced Pg1 altered pyloric glands (PAPG), ad enomatous hyperplasias and well-differentiated adenocarcinomas. Catech ol also induced PAPG and adenomatous hyperplasias although cancers did not develop. Adenomatous hyperplasias and adenocarcinomas all consist ed of gastric type cells resembling surface mucous cells or pyloric gl and cells with little or no Pg1 expression. In MNNG-induced stomach ca ncers generally lacking Pg1, altered Pg1 gene methylation was observed with both CCGG and GCGC sites being methylated more than normal pylor ic mucosa. MNNG or catechol-induced adenomatous hyperplasias also demo nstrated essentially the same methylation changes in the CCGG, but not in the GCGC sites. In the mucosa containing PAPG in groups treated wi th MNNG or catechol the methylation patterns of the Pg1 gene were quit e similar to those of normal pyloric mucosa, although the CCGG sites t ended to demonstrate slightly increased methylation. The results sugge st that the altered methylation of the Pg1 gene observed in stomach ca ncers is acquired early in the carcinogenic process and progressive me thylation changes occur with tumor development.