Characteristic association between K- ras gene mutation with loss of heterozygosity in X-ray-induced thymic lymphomas of the B6C3F1 mouse

Abstract

Purpose : To elucidate the characteristics of radiation carcinogenesis, the spectra of K- and N- ras oncogene mutations, loss of heterozygosity (LOH) and their association in X-ray-induced thymic lymphomas (TL) were determined by comparing with those of N -ethyl- N -nitrosourea (ENU)-induced and spontaneously occurring TL. Materials and methods : TL that arose in untreated, X-ray-irradiated and ENU-treated B6C3F1 mice were examined both for K- and N- ras mutations by PCR-SSCP and DNA sequencing and for LOH by PCR with polymorphic microsatellite markers. Results : (1) ras gene mutations were found in a proportion of TL from X-ray-exposed (~20%) and ENU-treated (30-40%) mice while no ras gene mutations were found in spontaneous TL. N- ras mutations were rare. (2) The spectrum of ras gene mutations was diverse and seemed to differ little between X-ray-induced and ENU-induced TL, even though there was a higher frequency of ras mutations in ENU-induced TL that clustered to K- ras codon 12. (3) The X-ray-induced TL showing K- ras mutation were associated with LOH on chromosome 6, while those showing no K- ras mutation were associated with high frequency of LOH on chromosomes 4, 11 and 12. Conclusion : These results demonstrate that, in the B6C3F1 mouse TL, X-ray-induced lymphomagenesis showed both the co-expression, yet low occurrence of allelic imbalance on chromosome 6 and K- ras mutation, and exclusive expression of frequent allelic imbalance on chromosomes 4, 11 and 12 and K- ras mutation.