KI-RAS MUTATIONS ARE AN EARLY EVENT AND CORRELATE WITH TUMOR STAGE INTRANSPLACENTALLY-INDUCED MURINE LUNG-TUMORS

A previous study from this laboratory demonstrated that treatment of p regnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring at 1 year after birth, the incidence of which correlated wit h fetal inducibility of Cyp1a1. Analysis by PCR amplification and alle le-specific hybridization (ASO) of paraffin-embedded tumors generated from that study revealed the presence of point mutations in exon 1 of the Ki-ras gene, This work has now been expanded by PCR amplification and ASO analysis of 31 additional lesions. Point mutations were found in 37 of the 47 (79%) lesions analyzed in this and the previous study, the majority of which were G-->T transversions in the first or second base of codon 12, The mutational spectrum appeared to be dependent on the relative stage of differentiation of the lesion, as both the inci dence of mutation and type of mutation produced correlated with malign ant progression, Mutations occurred in 60 % of the hyperplasias, 80 % of the adenomas and 100 % of the adenocarcinomas. In the lesions with mutations, GLY(12)-->CYS12 transversions occurred in 100 % of the hype rplasias, 42% of the adenomas and 13% of the adenocarcinomas. The GLY( 12)-->VAL(12) transversions occurred in none of the hyperplasias, 42% of the adenomas and 57% of the adenocarcinomas. The remaining mutation s, which consisted of ASP(12) transitions and ARG(13) transversions, o ccurred only in adenomas (17 %) and adenocarcinomas (29 %), Between th is study and our previous analyses, the identity of the mutations obta ined by ASO were confirmed by sequence analysis of eight of the 37 les ions that harbored mutations at the Ki-ras gene locus, There were no d ifferences in the type or incidence of mutations relative to the metab olic phenotype or sex of the mice, These data suggest that mutational activation of the Ki-ms gene locus is an early event in transplacental lung tumorigenesis, and that the type of mutations produced by exposu re to chemical carcinogens can influence the carcinogenic potential of the tumor, This may have prognostic significance in determining the m alignant progression of the neoplasm.