KI-RAS ONCOGENE ACTIVATION IN TRANSPLANTABLE RAT-THYROID CARCINOMA INDUCED BY N-BIS(2-HYDROXYPROPYL)NITROSAMINE

We have established 17 transplantable rat thyroid carcinoma cell lines from primary thyroid tumors of rats induced by N-bis(2-hydroxypropyl) nitrosamine (DHPN) (Cancer Res. (1993) 53, 4408-4412). The present stu dy was designed to evaluate point mutations in the murine c-Ki-ras gen e of these carcinoma cell lines. Using PCR amplification and direct se quencing, we found that the activated form of the Ki-ras oncogene was present in 4 (23%) of a total of 17 cell lines, all the Ki-ras gene mu tations being GC --> AT transitions. In three of the cell lines, the m utations occurred in codon 12 (GTP-binding domain), and in the remaini ng one the first nucleotide of codon 63 was affected. Histologically, three of the carcinomas with Ki-ras mutation were diagnosed as well-di fferentiated carcinomas, and the other as poorly differentiated carcin oma. Mutations of the ras gene are relatively uncommon in tumors of th ese histological types. From these experimental results, we suggest th at the mutation induced by DHPN is due to damage to guanine in cellula r DNA. In addition, Ki-ras activation may play an important role in th e initiation of thyroid carcinogenesis.