Ki-ras and p53 mutations are early and late events, respectively, in urethane-induced pulmonary carcinogenesis in A/J mice.
In the A/J strain of mice, urethane (ethyl carbamate) induces lung hyperplasia, adenoma, and adenocarcinoma in a time-dependent manner. These distinct morphological stages may correlate with sequential molecular genetic changes in this mouse model. To test this hypothesis, we investigated the presence of mutations involving Ki-ras and p53 in urethane-induced lung lesions in A/J mice at early and late stages of tumorigenesis. We precisely microdissected 40 lung lesions from paraffin-embedded sections. Ki-ras mutations around codon 61 and p53 mutations in exons 5-8 were identified by polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing techniques. In 29 early-stage lung lesions classified as hyperplasias (seven) or adenomas (22), we observed 19 Ki-ras mutations (66%), including three silent mutations and one double mutation at different codons, and one silent p53 mutation (3.5%). In 11 late-stage adenomas, we identified nine activating Ki-ras mutations (82%) and four missense p53 mutations (36%). These results indicate that Ki-ras mutations arise early, whereas p53 mutations occur relatively late during the benign stages of urethane-induced lung carcinogenesis in A/J mice.
Horio
Y
Y
Department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Chen
A
A
Rice
P
P
Roth
J A
JA
Malkinson
A M
AM
Schrump
D S
DS
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000236:Adenoma / Q000150:complications / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D018450:Disease Progression; D005091:Exons; D016158:Genes, p53 / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D006965:Hyperplasia; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D009154:Mutation; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics; D013997:Time Factors; D014520:Urethane / Q000633:toxicity*
D002273:Carcinogens; D014520:Urethane