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.
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.
Kitada
H
H
Department of Oncological Pathology, Nara Medical University, Japan.
Tsutsumi
M
M
Tsujiuchi
T
T
Takahama
M
M
Fukuda
T
T
Narita
N
N
Konsihi
Y
Y
D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D016158:Genes, p53; D011905:Genes, ras; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009153:Mutagens; D009154:Mutation; D009602:Nitrosamines; D018807:Polymorphism, Single-Stranded Conformational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D017931:DNA Primers; D009153:Mutagens; D009602:Nitrosamines; D016159:Tumor Suppressor Protein p53; C012457:diisopropanolnitrosamine; D016283:Proto-Oncogene Proteins p21(ras)