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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

¹ Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
² Experimental Pathology Laboratories, Inc., Research Triangle Park, NC 27709, USA

Correspondence: Address correspondence to: Hue-Hua L. Hong, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; e-mail:hong5{at}niehs.nih.gov

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.

Key Words: K-ras • ethylene oxide • mice • carcinogen • Harderian gland • lung • uterus • neoplasm

Abbreviations: EO, ethylene oxide • PCR, polymerase chain reaction • DNA, deoxyribonucleic acid • RNA, ribonucleic acid • A, C, G, T, , adenine, cytosine, guanine, thymine • NTP, National Toxicology Program • HG, Harderian gland • ddNTP, dideoxynucleotide • HEG, N 7-(2-hydroxyethyl) guanine

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