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

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2007; 35(1):81-5. DOI: 10.1080/01926230601063839
Source: PubMed


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.

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Available from: Christopher D Houle, Sep 01, 2014
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    • "lected for use in this study as it is a direct acting genotoxic agent with known mutagenic properties in vitro and in vivo [ Victorin and Stahlberg , 1988 ; Agurell et al . , 1991 ; Thier and Bolt , 2000 ] . A 2 - year exposure to EtO was found to preferentially induce GGT ! GTT mutations at codon 12 of K - ras in the lung tumours of B6C3F1 mice [ Hong et al . , 2007 ] . As Ras mutations are found in approxi - mately 30% of human nonsmall cell lung cancers [ Sagawa et al . , 1998 ] , this finding may be of relevance to human lung carcinogenesis . The nature of the EtO induced mutations at codon 12 of K - ras has recently been explored further , and it appears that the selective expan - sion of mutan"
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