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
Im. Mckenna et al., 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, MUT RES-GTE, 490(1), 2001, pp. 57-65
Citations number
47
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
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.