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Role of mutations at codon 61 of the c-Ha-ras gene during diethylnitrosamine-induced hepatocarcinogenesis in C3H/He mice

Authors

  • Richard Bauer-Hofmann,

    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
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  • Fritz Klimek,

    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
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  • Albrecht Buchmann,

    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
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  • Oliver Müller,

    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
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  • Peter Bannasch,

    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
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  • Michael Schwarz

    Corresponding author
    1. Project Group “Tumor Promotion in the Liver” (RB-H, OM, MS) and Division of Cytopathology (FK, PB), German Cancer Research Center, Heidelberg; and Institute of Toxicology (AB), University of Tubingen, Tubingen, Germany
    • German Cancer Research Center, Project Group “Tumor Promotion in the Liver,” Im Neuenheimer Feld 280, 6900 Heidelberg, Germany
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Abstract

Liver tumors of certain strains of mice frequently contain mutations at codon 61 of the c-Ha-ras gene. In our study, we investigated the significance of these mutations in the carcinogenic process. Male C3H/He mice received a single injection of diethylnitrosamine (DEN) on day 15 after birth, and groups of animals were killed at various time intervals between 11 and 52 wk after treatment. At the earlier time points (11–29 wk), we analyzed microdissected tissue from precancerous glucose-6-phosphatase-deficient liver lesions larger than approximately 200 p.m in diameter, for the presence and pattern of c-Ha-ras codon 61 mutations. In parallel, the growth characteristics of these liver lesions were studied by pulse labeling with [3H]thymidine and by determining the size distribution of the lesions. At the later time points (42–52 wk after DEN treatment), liver tumors were dissected and also analyzed for the presence of c-Ha-ras mutations. We found mutations to be already present in some of the enzyme-altered liver lesions at weeks 11–29, suggesting that the mutations occurred early in the carcinogenic process. Whereas about 10% of the precancerous focal liver lesions showed mutations in the c-Ha-ras gene, the mutation frequency was increased to about 50% in the later-appearing hepatocellular adenomas and carcinomas, suggesting that c-Ha-ras codon 61 mutations may provide a selective advantage to the mutated cell clones. © 1992 Wiley-Liss, Inc.

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