Chemically induced tumors in transgenic mice carrying prototype human c-Ha-ras genes

Three independent transgenic mouse lines carrying human prototype c-Ha-ras genes were established. Approximately 50% of the transgenic offspring of these lines developed spontaneous tumors within 18 months. Types of tumors were restricted to angiosarcomas, skin papillomas and lung or Harderian adenocarcinomas. Interestingly, all angiosarcomas (16/16) had point mutations at the 61st codon of the transgenes. Furthermore, they were also very susceptible to the chemical carcinogens, N-methyl-N'-nitrosourea (MNU) and dimethyl-benzanthracene (DMBA). Within 12 weeks after administration of MNU, the transgenic mice developed forestomach papillomas and then carcinomas very frequently, at the rate of almost 100% and almost all of the tumors had point mutations in their transgenes at the 12th codon from GGC (Gly) to GAC (Asp). All the carcinomas of the forestomach, lung and spleen induced by DMBA had point mutations at the 61st codon from CAG (Gln) to CTG (Leu). Because no somatic point mutations in the transgenes have ever been detected in normal tissues of the affected mice, these mutations seemingly activated the human prototype c-Ha-ras transgene. From these results, it is suggested that the somatic mutation of the human c-Ha-ras transgene plays a causative role in the occurrence of natural tumors and those induced by MNU or DMBA administration in transgenic mice. This transgenic mouse provides a unique screening system for chemicals that induce or suppress the tumorigenesis.