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), and 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 A182-->T and A182-->G mutations. In addition, one promoter-induced tumor had a G35-->A mutation in codon 12, and one had a G37-->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 G37-->C transversion and two had G38-->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 A182-->T transversions in codon 61 except for two 7-MBA-initiated papillomas that had G37-->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.
DiGiovanni
J
J
Department of Carcinogenesis, Science Park- Research Division, University of Texas M. D. Anderson Cancer Center, Smithville 78957.
Beltrán
L
L
Rupp
A
A
Harvey
R G
RG
Gill
R D
RD
D000818:Animals; D001483:Base Sequence; D001551:Benz(a)Anthracenes; D001564:Benzo(a)pyrene; D002273:Carcinogens; D003062:Codon / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects; D010212:Papilloma / Q000139:chemically induced* / Q000235:genetics*; D011083:Polycyclic Compounds; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D012879:Skin Physiological Phenomena
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D003062:Codon; D004273:DNA, Neoplasm; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; C021219:7-methylbenzanthracene