H-RAS AND K-RAS MUTATIONAL PROFILES IN CHEMICALLY-INDUCED LIVER-TUMORS FROM B6C3F(1) AND CD-1 MICE

Liver tumors from mice treated with genotoxic carcinogens often posses s mutations in ras protooncogenes, and these sequence alterations in r as frequently reflect the mutational specificity of the carcinogen. Pr evious studies suggest that the mouse model used for tumor induction m ay affect ras mutational patterns. In order to explore this possibilit y, H- and K-ras mutational profiles were established in liver tumors f rom male B6C3F(1) and CD-I mice administered benzo[a]pyrene (BaP) 6-ni trochrysene (6-NC), and 4-aminobiphenyl (4-ABP). With the exception of B-NC-induced tumors in B6C3F(1) mice, a high proportion of the tumors induced in both types of mice contained ras mutations. In CD-1 mice, 6-NC predominantly induced C-->A mutations in H-ras codon 61 (90% of t umors analyzed), whereas 4-ABP mainly induced A-->T mutations in H-ras codon 61 (50%) and BaP induced both A-->T (27%) and G-->C (50%) mutat ions in H-ras codon 61 and K-ras codon 13, respectively. In B6C3F, mic e, 85% of BaP tumors had G-->C mutations in K-ras codon 13 and 85% of 4-ABP tumors had C-->A mutations in H-ras codon 61, while among 6-NC t umors, only 4% had G-->C mutations in K-ras codon 13 and none had H-ra s mutations. Statistical analysis of these results indicates that the patterns of tumor ras mutations induced by BaP in CD-1 and B6C3F(1) mi ce were indistinguishable, while 6-NC and 4-ABP produced different tum or ras profiles in the two mouse models. Published mutational profiles for active metabolites of BaP and 6-NC from in vitro reporter gene sy stems were inconsistent with both the CD-1 and B6C3F(1) tumor ras muta tional responses.