K-ras mutations in lung tumors and tumors from other organs are consistent with a common mechanism of ethylene oxide tumorigenesis in the B6C3F1 mouse.
Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K-ras mutations in codons 12, 13, and 61. K-ras mutations were identified in 100% (23/23) of the EO-induced lung neoplasms and 25% (27/108) of the spontaneous lung neoplasms. Codon 12 G to T transversions were common in EO-induced lung neoplasms (21/23) but infrequent in spontaneous lung neoplasms (1/108). K-ras mutations were found in 86% (18/21) of the EO-induced HG neoplasms and 7% (2/27) of the spontaneous HG neoplasms. Codon 13 G to C and codon 12 G to T transversions were predominant in the EO-induced HG neoplasms but absent in spontaneous HG neoplasms (0/27). K-ras mutations occurred in 83% (5/6) of the EO-induced uterine carcinomas and all were codon 13 C to T transitions. These data show a strong predilection for development of K-ras mutations in EO-induced lung, Harderian gland, and uterine neoplasms. This suggests that EO specifically targets the K-ras gene in multiple tissue types and that this event is a critical component of EO-induced tumorigenesis.
Hong
Hue-Hua L
HH
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. hong5@niehs.nih.gov
Houle
Christopher D
CD
Ton
Thai-Vu T
TV
Sills
Robert C
RC
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000032:analysis; D004202:Disinfectants / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000633:toxicity*; D005260:Female; D011905:Genes, ras; D006243:Harderian Gland / Q000187:drug effects / Q000473:pathology; D019570:Inhalation Exposure; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D012626:Sebaceous Gland Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens; D004273:DNA, Neoplasm; D004202:Disinfectants; D005027:Ethylene Oxide