Ki-ras and p53 mutations are early and late events, respectively, in urethane-induced pulmonary carcinogenesis in A/J mice

✍ Scribed by Yoshitsugu Horio; Aaron Chen; Pamela Rice; Jack A. Roth; Alvin M. Malkinson; David S. Schrump

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 820 KB
• Volume: 17
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199612)17:4<217::aid-mc5>3.0.co;2-a

✦ Synopsis

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 N J mice at early and late stages of tumorigenesis.

We precisely microdissected 40 lung lesions from paraff in-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 Kiras mutations arise early, whereas p53 mutations occur relatively late during the benign stages of urethaneinduced lung carcinogenesis in N J mice.