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

Preconceptional exposure of male NIH swiss mice to chromium(III) chloride r esulted 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 R-ras protooncogene are frequen t, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis b y chromium(III). These offspring had lived until natural death at advanced ages (average 816 +/- 175 days for controls, 904 +/- 164 for progeny of chr omium-treated fathers). Mutations of K-ras, analyzed by single-strand confo rmation polymorphism and sequencing, were, in codon 12, wild type GGT (glyc ine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and i n codon 61, wild-type CAA (glutamine), to CGA (arginine). K-rns mutation fr equencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or ten dency to spontaneous mutation in K-ras does not seem to be part of the mech anism of preconceptional carcinogenesis here. However, an additional intere sting 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 combi ned. This was not related to age of the tumor-bearing mice or the size of t he tumors. K-ras mutations may contribute to malignant tumor progression du ring aging, of possible relevance to the putative association of such mutat ions with poor prognosis of human lung adenocarcinomas. (C) 2001 Elsevier S cience B.V. All rights reserved.