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Point Mutations of the c-H-ras Gene in Spontaneous Liver Tumors of Transgenic Mice Carrying the Human c-H-ras GenePharmacology Laboratories, Takeda Chemical Industries Ltd., 2-17-85 Juso Honmachi, Yodogawa-ku, Osaka 532–8686, Japan
Hikari Branch, Drug Safety Research Laboratories, Takeda Chemical Industries Ltd., 4720 Mitsui, Hikari, Yamaguchi 743–8502, Japan
Hikari Branch, Drug Safety Research Laboratories, Takeda Chemical Industries Ltd., 4720 Mitsui, Hikari, Yamaguchi 743–8502, Japan
Division of Pathology, National institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158–8501, Japan Spontaneous proliferative liver lesions were found in 15 (13 males and 2 females) of 244 (122 of each sex) transgenic (Tg) mice carrying the human prototype c-H-ras gene (rasH2). The liver lesions included 3 foci of cellular alteration, 1 hepatocellular adenoma, 5 hepatocellular carcinomas, and 4 hepatic hemangiosarcomas in the males and 1 focus of cellular alteration and 1 hepatocellular carcinoma in the females. The mutation patterns of the human and endogenous mouse c-H-ras codon 61 in these proliferative liver lesions were analyzed by DNA amplification using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP), and oligonucleotide dot blot hybridization. The hepatocellular carcinomas in 4 males and 1 female contained a point mutation in the mouse c-H-ras gene: 3, 1, and 1 carcinomas had a CAA to AAA transversion at the first base of codon 61, a CAA to CTA transversion, and a CAA to CGA transition at the second base of codon 61, respectively. No point mutations in the human c-H-ras transgene were detected in any hepatocellular carcinoma. All 4 hepatic hemangiosarcomas had a CAG to CTG transversion at codon 61 of the human c-H-ras gene, but no point mutations were detected in codon 61 of the mouse c-H-ras gene. No mutations in human or mouse c-H-ras codon 61 were detected in altered cell foci or hepatocellular adenoma. These results indicate that spontaneous liver tumors in rasH2 Tg mice contain different mutation patterns depending on the histologic type or cell origin of the tumors (i.e., hepatocellular carcinomas or hepatic hemangiosarcomas). The absence of similar mutations in foci of cellular alteration and the hepatocellular adenoma suggests that the occurrence of codon 61 point mutations is a late event in the progression of hepatocellular neoplasia in rasH2 Tg mice.
Key Words: Human prototype c-H-ras transgenic (rasH2 Tg) • mouse • hepatocellular carcinoma • hepatic hemangiosarcoma • polymerase chain reaction • single-strand conformation polymorphism (PCR-SSCP) • nonradioactive oligonucleotide dot blot hybridization
Toxicologic Pathology, Vol. 26, No. 4,
556-561 (1998) This article has been cited by other articles:
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