The Kras mutational spectra of chemically induced lung tumors in different inbred mice mimics the spectra of KRAS mutations in adenocarcinomas in smokers versus nonsmokers.
BACKGROUND
Human lung cancer patients exhibit different KRAS mutations depending on smoking status. In a mouse model of human cancer, A/J and BALB/cBy mice treated with the tobacco carcinogen, 3-methylcholanthrene (MCA), followed by butylated hydroxytoluene (BHT)-elicited chronic inflammation develop a high multiplicity of lung tumors.


METHODS
DNA was isolated from MCA-induced lung tumors in A/J and BALB/cByJ mice. Kras codon 12 sequences from these tumors were compared to those in human lung tumors from smokers and never-smokers.


RESULTS
The distribution of Kras codon 12 mutations in MCA-induced A/J lung tumors is strikingly similar to those found in adenocarcinomas from human smokers. In contrast, codon 12 mutations in BALB/cBy mice contain predominantly G --> D mutations, which is the most common mutation in never smokers.


CONCLUSIONS
A single lung carcinogen induces different tumor initiating mutations in different strains of mice. This may be useful for investigating the role of specific KRAS mutations in adenocarcinoma pathogenesis in smokers versus never smokers, identifying mechanisms that select for certain KRAS mutations and developing new drugs that specifically target cells with different KRAS mutations.
Fritz
Jason M
JM
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
Dwyer-Nield
Lori D
LD
Russell
Bridgette M
BM
Malkinson
Alvin M
AM
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D003062:Codon; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012907:Smoking; D018631:ras Proteins / Q000235:genetics*
D003062:Codon; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D002084:Butylated Hydroxytoluene; D008748:Methylcholanthrene; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins