Genetic Alterations of p53 and ras Genes in 1,3-Butadiene- and 2′,3′-Dideoxycytidine-induced Lymphomas

Mutations of p53 and ras genes were analyzed in 40 and 31 1,3-butadiene (BD)-induced lymphomas of B6C3F1 mice (BLFs), respectively, and in 63 2',3'-dideoxycytidine-induced lymphomas, which were collected from B6C3F1 (n = 16) or NIH Swiss mice (DLSs; n = 47). The frequencies of K- and N-ras mutations in BLFs (32 and 13%, respectively) were higher than those in DLSs (13 and 2%, respectively). Seven of 10 K-ras-mutated BLFs contained codon 13 CGC mutations, whereas no mutation in K-ras codon 13 was detected in DLSs, suggesting that the codon 13 CGC mutation is specific for BD exposure. Interestingly, 8 of 13 BLFs with ras mutations were from low-dose (≤200 ppm) or stop-exposure (26 weeks) groups. These results suggest that ras mutations play an important role in the development of BD-induced lymphoma and may represent an early event. Analysis of genetic alterations in exons 5-8 of the p53 gene revealed mutations in seven of the BLFs and three of the DLSs. All seven BLFs carrying p53 mutations were collected from the high-dose (625 ppm) continuous exposure group, which might indicate that p53 is involved in the progression of BD-induced lymphoma and in late stage of lymphomagenesis. Mutations in ras and p53 genes are relatively infrequent in 2',3'-dideoxycytidine-induced lymphomas, suggesting that other genes must be involved.