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- Title
Mutations of ras Protooncogenes and p53 Tumor Suppressor Gene in Cardiac Hemangiosarcomas from B6C3F1 Mice Exposed to 1,3-Butadiene for 2 Years.
- Authors
Hong, Hue-Hua L.; Devereux, Theodora R.; Melnick, Ronald L.; Moomaw, Cindy R.; Boorman, Gary A.; Sills, Robert C.
- Abstract
1,3-Butadiene is a multisite carcinogen in rodents. Incidences of cardiac hemangiosarcomas were significantly increased in male and female B6C3F1 mice that inhaled 1,3-butadiene (BD) for 2 years. Eleven BD-induced cardiac hemangiosarcomas were examined for genetic alterations in ras protooncogenes and in the p53 tumor suppressor gene. Nine of 11 (82%) BD-induced hemangiosarcomas had K-ras mutations and 5 of 11 (46%) had H-ras mutations. All of the K-ras mutations were G→C transversions (GGC→CGC) at codon 13; this pattern is consistent with reported results in BD-induced lung neoplasms and lymphomas. Both K- ras codon 13 CGC mutations and H-ras codon 61 CGA mutations were detected in 5 of 9 (56%) hemangiosarcomas. The 11 hemangiosarcomas stained positive for p53 protein by immunohistochemistry and were analyzed for p53 mutations using cycle sequencing of polymerase chain reaction (PCR) amplified DNA isolated from paraffin-embedded sections. Mutations in exons 5 to 8 of the p53 gene were identified in 5 of 11 (46%) hemangiosarcomas, and all of these were from the 200- or 625-ppm exposure groups that also had K-ras codon 13 CGC mutations. Our data indicate that K-ras, H- ras, and p53 mutations in these hemangiosarcomas most likely occurred as a result of the genotoxic effects of BD and that these mutations may play a role in the pathogenesis of BD-induced cardiac hemangiosarcomas in the B6C3F1 mouse.
- Publication
Toxicologic Pathology, 2000, Vol 28, Issue 4, p529
- ISSN
0192-6233
- Publication type
Article
- DOI
10.1177/019262330002800404