Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years

1,3-Butadiene is a multisite carcinogen in rodents. Incidences of cardiac h emangiosarcomas were significantly increased in male and female B6C3F1 mice that inhaled 1,3-butadiene (BD) for 2 years. Eleven ED-induced cardiac hem angiosarcomas were examined for genetic alterations in ras protooncogenes a nd in the p53 tumor suppressor gene. Nine of 11 (82%) ED-induced hemangiosa rcomas had K-ras mutations and 5 of 11 (46%) had H-ras mutations. All of th e K-ras mutations were G --> C transversions (GGC --> CGC) at codon 13; thi s pattern is consistent with reported results in ED-induced lung neoplasms and lymphomas. Both K-ras codon 13 CGC mutations and H-ras codon 61 CGA mut ations were detected in 5 of 9 (56%) hemangiosarcomas. The 11 hemangiosarco mas stained positive for p53 protein by immunohistochemistry and were analy zed for p53 mutations using cycle sequencing of polymerase chain reaction ( PCR) amplified DNA isolated from paraffin-embedded sections. Mutations in e xons 5 to 8 of the p53 gene were identified in 5 of 11 (46%) hemangiosarcom as, and all of these were from the 200- or 625-ppm exposure groups that als o 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 o f the genotoxic effects of ED and that these mutations may play a role in t he pathogenesis of ED-induced cardiac hemangiosarcomas in the B6C3F1 mouse.