Activation of the ras family of oncogenes occurs frequently in liver
tumors of the B6C3F1 mouse, a strain which is highly sensitive to hepatocarcinogenesis. Many other mouse strains are much more resistant to hepatocarcinogenesis; the aim of this study was to determine the frequency and pattern of oncogene activation in spontaneous and chemically induced liver
tumors of three such strains, the C57BL/6J, the C57BL/6 x DBA/2 F1 hybrid (B6D2F1) and the C57BL/6 x Balb/c F1 hybrid (B6BCF1). The C57BL/6, DBA/2 and Balb/c strains are all relatively resistant to spontaneous hepatocarcinogenesis (1.5-3.6% of animals develop liver
tumors in 2 years); with regard to chemically induced hepatocarcinogenesis the Balb/c is highly resistant, the C57BL/6 has low susceptibility and the DBA/2 has low to moderate susceptibility. The nude mouse tumorigenicity assay was used to search for activated oncogenes in 15 C57BL/6J liver
tumors induced by a single neonatal dose of
vinyl carbamate (VC, 0.15 mumol/g
body weight). Three
tumors contained H-ras genes activated by point mutations at
codon 61 and one contained a non-ras oncogene. The polymerase chain reaction and allele-specific
oligonucleotide hybridization were used to study H-ras mutations in spontaneous and VC-induced
tumors from all three strains of mice. The frequency of H-ras
codon 61 mutations in
tumors induced by 0.15 mumol/g
body weight VC in the C57BL/6J mouse (5/37) was similar to that in spontaneous
tumors (2/9); surprisingly,
tumors induced by a lower dose of VC (0.03 mumol/g
body weight) had a higher frequency of H-ras mutations (12/28). The frequencies of H-ras activation detected in VC (0.03 mumol/g
body weight)-induced
tumors from the two F1 hybrids studied differed markedly. Only one VC-induced B6BCF1
tumor contained a mutated H-ras gene (1/10), whereas the majority of B6D2F1
tumors contained such mutations (23/33). Several spontaneous B6D2F1 liver
tumors contained H-ras
codon 61 mutations (6/15). Thus, H-ras activation frequency does not determine susceptibility to hepatocarcinogenesis in inbred mice and their F1 hybrids, since a relatively high frequency of H-ras mutations was observed in two resistant strains and a low frequency was found in the other strain.