SELECTIVE MUTATION OF K-RAS BY N-ETHYLNITROSOUREA SHIFTS FROM CODON-12 TO CODON-61 DURING FETAL MOUSE LUNG MATURATION

Fetal mouse lung before gestation day 17 shows unique sensitivity to c ausation of rapidly growing tumors by N-ethylnitrosourea (ENU). Since mouse lung tumors present a mutated K-ras oncogene, we hypothesized th at this special susceptibility might reflect an unusual vulnerability of the K-ras gene. Of the lung tumors caused by ENU exposure of BALB/c mice on gestation day 14, 8/25 had a codon 12 mutation in K-ras, vs 4 /25 in codon 61, Of 15 tumors after day 16 exposure, three had codon 1 2 and four codon 61 changes. Tumors from day 18 exposure had only codo n 61 mutations (11/16), all A:T to G:C changes (CGA), By contrast, cod on 12 (GGT) changes included G:C to T:A, to A:T,and to C:G, These resu lts show significant (P<0.01) shift in the sensitivity of particular K -ras codons to ENU mutation, during fetal mouse lung maturation. In a test of a possible relationship to expression of K-ras, K-ras p21 was measured in lungs of fetal mice, and found to increase markedly on day 18 in comparison to days 14 and 16, Both alkylation of DIVA and base damage due to reactive oxygen species are postulated as mechanisms for mutation by ENU, whose efficacies vary with state of fetal lung matur ation and K-rns expression.