VARIANT MUTATIONAL ACTIVATION OF THE K-RAS ONCOGENE IN RENAL MESENCHYMAL TUMORS INDUCED IN NEWBORN F344 RATS BY METHYL(METHOXYMETHYL)NITROSAMINE

Renal mesenchymal tumors were induced at high incidence in F344 rats b y a single intraperitoneal injection of methyl(methoxymethyl) nitrosam ine (DMN-OMe) within 48 h after birth, DNAs from 18 of 35 mesenchymal tumors contained transforming ras sequences in NIH3T3 transfection ass ays: K-ras (17/18) or N-ras (1/18), Single-stranded conformational pol ymorphism analysis or dideoxy sequencing of polymerase chain reaction- amplified K-rns gene fragments revealed that these neoplasms contained a variety of activating mutations in the K-ras oncogene, Alterations in codon 12 predominated and included GGT --> GAT transitions, GGT --> GTT or TGT transversions, and previously reported insertion mutations , although some tumors expressed more than one mutation and the patter n of mutations even varied within tumors, Mutations were also found in exons 2 and 3, In addition, tumor transplantability into syngeneic ho sts correlated positively and significantly with K-ms activation, Rena l mesenchymal tumors with transforming mutations in exon 1 were often successfully passaged (10/12) while tumors which lacked mutations in e xon 1 were infrequently transplantable (2/14), While the observed base substitutions in K-rns are consistent with adduct formation, the pres ence of insertion mutations and intratumor heterogeneity of alteration s suggest that ras activation in DMN-OMe-induced tumors is not necessa rily an early event in tumorigenesis.