Frequent mutations of Ki-ras but no mutations of Ha-ras and p53 in lung lesions induced by N-nitrosobis(2-hydroxypropyl)amine in rats

Mol Carcinog. 1996 Apr;15(4):276-83. doi: 10.1002/(SICI)1098-2744(199604)15:4<276::AID-MC5>3.0.CO;2-E.

Abstract

Point mutations of the Ki-ras and p53 genes in rat lung lesions induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) were investigated by polymerase chain reaction-single strand conformation polymorphism analysis followed by direct sequencing using paraffin-embedded tissues. Male Wistar rats 6 wk old were given 2000 ppm BHP in drinking water for 15 wk. Another group was given drinking water without BHP. The rats were killed 20-27 wk after the beginning of the experiment. Lung adenomatous and squamous lesions, including carcinomas, were induced. The frequencies of Ki-ras mutations were 40% (six of 15) in alveolar hyperplasias, 36% (five of 14) in adenomas, 72% (18 of 25) in adenocarcinomas, 20% (three of 15) in squamous metaplasias, 50% (three of six) in squamous cell carcinomas, and 50% (five of 10) in adenosquamous carcinomas. The mutations were all G-->A transitions at the second position of codon 12; no other mutations were detected. However, Ha-ras mutations in exons 1 and 2 and p53 mutations in exons 5, 6, and 7 were not detected in adenocarcinomas and squamous cell carcinomas. These results indicate that Ki-ras mutation is an early genetic event in some adenomatous and squamous lung carcinogeneses and that Ki-ras mutations can cause benign lesions to convert to malignant lesions. The results also show that Ha-ras and p53 mutations are not involved in rat lung carcinogenesis induced by BHP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Animals
  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • DNA Primers / chemistry
  • Genes, p53*
  • Genes, ras*
  • Lung Neoplasms / genetics*
  • Male
  • Molecular Sequence Data
  • Mutagens*
  • Mutation
  • Nitrosamines*
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Rats
  • Rats, Wistar
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • DNA Primers
  • Mutagens
  • Nitrosamines
  • Tumor Suppressor Protein p53
  • diisopropanolnitrosamine
  • Proto-Oncogene Proteins p21(ras)