title: K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas.
abstract: Preconceptional exposure of male NIH Swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the K-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816+/-175 days for controls, 904+/-164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-ras mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P=0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas.
authors.affiliation: Office of Pollution Prevention and Toxic Substances, Environmental Protection Agency, Washington, DC 20460, USA. mckenna.ilda@epa.gov
authors.forename: I M
authors.initials: IM
authors.lastname: McKenna
authors.forename: G
authors.initials: G
authors.lastname: Ramakrishna
authors.forename: B A
authors.initials: BA
authors.lastname: Diwan
authors.forename: Y H
authors.initials: YH
authors.lastname: Shiao
authors.forename: K S
authors.initials: KS
authors.lastname: Kasprzak
authors.forename: D A
authors.initials: DA
authors.lastname: Powell
authors.forename: L M
authors.initials: LM
authors.lastname: Anderson
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000235:genetics*; D000367:Age Factors; D000818:Animals; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics*; D002857:Chromium / Q000633:toxicity*; D005260:Female; D011905:Genes, ras; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D018812:Paternal Exposure; D017354:Point Mutation
chemical_list: D002857:Chromium