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Mutations of ras Protooncogenes and p53 Tumor Suppressor Gene in Cardiac Hemangiosarcomas from B6C3F1 Mice Exposed to 1,3-Butadiene for 2 Years

Environmental Toxicology Program, National Institute of Enviromental Health Sciences, Research Trinangle Park, North Carolina 27709

Theodora R. Devereux

Environmental Carcinogenesis Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Ronald L. Melnick

Environmental Toxicology Program, National Institute of Enviromental Health Sciences, Research Trinangle Park, North Carolina 27709

Cindy R. Moomaw

Environmental Toxicology Program, National Institute of Enviromental Health Sciences, Research Trinangle Park, North Carolina 27709

Gary A. Boorman

Environmental Toxicology Program, National Institute of Enviromental Health Sciences, Research Trinangle Park, North Carolina 27709

Robert C. Sills

Environmental Toxicology Program, National Institute of Enviromental Health Sciences, Research Trinangle Park, North Carolina 27709

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 GC transversions (GGCCGC) 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.

Key Words: Cardiac hemangiosarcoma • 1,3-butadiene • p53 • ras

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