FURTHER ANALYSIS OF C-HA-RAS MUTATIONS IN PAPILLOMAS INITIATED BY SEVERAL POLYCYCLIC AROMATIC-HYDROCARBONS AND PAPILLOMAS FROM UNINITIATED, PROMOTER-TREATED SKIN IN SENCAR MICE

In this study we analyzed the mutations in c-Ha-ras from skin papillomas initiated with benzo[a]pyrene (B[a]P), 7-methylbenz[a]anthracene (7-MBA), a nd 10-fluoro-7-methylbenz[a]anthracene(10-F-7-MBA) and from papillomas induced by treatment with tumor promoter alone. Among the papillomas induced by treatment with tumor promoter alone, 56% (nine of 16) had mutations in c-Ha-ras. These mutations were found primarily in codon 61 and included both A(182)-->T and A(182)-->G mutations. In addition, one promoter-induced tumor had a G(35)-->A mutation in codon 12, and one had a G(37)-->C mutation in codon 13. The other promoter-induced papillomas did not have detectable mutations in codons 12, 13, or 61. Most of the B[a]P-initiated papillomas (77%; 10 of 13) did not have detectable mutations in c-Ha-ras codons 12, 13, or 61. However, three of these B[a]P-initiated papillomas had c-Ha-ras codon 13 mutations; one had a G(37)-->C transversion and two had G(38)-->T transversions. Most of the 7-MBA-initiated tumors and all of the 10-F-7-MBA-initiated tumors had an activated c-Ha-ras gene [nine of 10 (90%) and 11 of 11 (100%), respectively]. These mutations were almost exclusively A(182)-->T transversions in codon 61 except for two 7-MBA-initiated papillomas that had G(37)-->C transversions in codon 13. The results suggest that more than one mechanism may contribute to activation of c-Ha-ras by polycyclic aromatic hydrocarbons (PAHs) in mouse skin. Furthermore, the absence of c-Ha-ras mutations in most B[a]P-initiated papillomas, as well as in a significant fraction of those induced by tumor promoter alone, suggests that there may be other molecular targets involved in tumor initiation by PAHs in mouse skin. (C) 1993 Wiley-Liss, Inc.