LACK OF P53 AND RAS MUTATIONS IN HELICOBACTER HEPATICUS-INDUCED LIVER-TUMORS IN A JCR MICE/

Helicobacter hepaticus is a recently discovered bacterium that invades mouse liver causing chronic active hepatitis followed by development of preneoplastic hepatocellular foci, hepatocellular adenomas and carc inomas. This establishes a unique animal model for study of the mechan isms of cancer development due to a chronic bacterial infection. A pos sible mechanism of bacteria-associated tumorigenesis is mutation of on cogenes or tumor suppressor genes. Since mutations in ras oncogenes ha ve been widely detected in a variety of chemically induced and spontan eous mouse liver tumors and specific mutations in the p53 tumor suppre ssor gene have been associated with human bladder cancers attributed t o chronic schistosomal infection, we studied exons 1 and 2 of the N-, K- and H-ras genes and exons 5-8 of the p53 gene for the presence of p oint mutations in 25 liver tumors from 10 naturally infected A/JCr mic e, ranging in age from 16 to 24 months. The 20 adenomas and five carci nomas varied in size from 0.1 to 2.3 cm and arose in livers characteri zed by a wide assortment of pathological profiles, including hepatitis , inflammation, hyperplasia, hypertrophy, leukocyte infiltration, necr osis and focal phenotypic alteration. DNA samples extracted from forma lin-fixed paraffin-embedded tissues were screened by PCR/SSCP analysis and showed no mutations in the analyzed genes. Complete absence of mu tations in ras genes in 25 mouse liver tumors is unusual. Other genes may be targeted or H.hepaticus infection causes liver cancer through o ther pathways than direct damage to DNA.