33. Characteristic Association between K-ras Gene Mutation with Loss of Heterozygosity in X-ray-Induced Thymic Lymphomas of the B6C3F1 Mouse

Yoshiya Shimada, Mayumi Nishimura, Shizuko Kakinuma, Takeshi Takeuchi, Toshiaki Ogiu, Gen Suzuki, Yukiko Nakata, Shun-ichi Sasanuma, kazuei Mita and Toshihiko Sado

Keywords: T-cell lymphoma, LOH, K-ras

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 some TL from X-ray-exposed (approximately 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 a 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 B6C3F1mouse TL, X-ray-induced lymphomagenesis showed both co-expression, with 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.