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
J. Digiovanni et al., 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, Molecular carcinogenesis, 8(4), 1993, pp. 272-279
In this study we analyzed the mutations in c-Ha-ras from skin papillom
as 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 p
apillomas induced by treatment with tumor promoter alone. Among the pa
pillomas 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 ad
dition, one promoter-induced tumor had a G(35)-->A mutation in codon 1
2, and one had a G(37)-->C mutation in codon 13. The other promoter-in
duced papillomas did not have detectable mutations in codons 12, 13, o
r 61. Most of the B[a]P-initiated papillomas (77%; 10 of 13) did not h
ave detectable mutations in c-Ha-ras codons 12, 13, or 61. However, th
ree of these B[a]P-initiated papillomas had c-Ha-ras codon 13 mutation
s; one had a G(37)-->C transversion and two had G(38)-->T transversion
s. Most of the 7-MBA-initiated tumors and all of the 10-F-7-MBA-initia
ted tumors had an activated c-Ha-ras gene [nine of 10 (90%) and 11 of
11 (100%), respectively]. These mutations were almost exclusively A(18
2)-->T transversions in codon 61 except for two 7-MBA-initiated papill
omas 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 promo
ter alone, suggests that there may be other molecular targets involved
in tumor initiation by PAHs in mouse skin. (C) 1993 Wiley-Liss, Inc.