Preferential induction of RET/PTC1 rearrangement by X-ray irradiation

Ionizing radiation is a well known risk factor of thyroid cancer developmen t, but the mechanism of radiation induced carcinogenesis is not clear. The RET/PTC oncogene, an activated form of the RET proto-oncogene, is frequentl y observed in papillary thyroid carcinoma (PTC); RET/PTC1, -2 and -3 are kn own to be the three major forms, High frequencies of RET/PTC rearrangements have been observed in radiation-associated PTC, such as those appearing po st-Chernobyl or post-radiotherapy, but the rearrangement types differ betwe en these two populations. We investigated whether a specific type of RET/PT C rearrangement was induced by X-rays in vivo and in vitro. ln human normal thyroid tissues transplanted in scid mice, the RET/PTC1 rearrangement was predominantly detected throughout the observation period (up to 60 days) af ter X-ray exposure of 50 Gy, On the other hand, RET/PTC3 was detected only 7 days after X-irradiation, and no transcript of RET/PTC2 was detected. The se results are supported by the results of an in vitro study, The RET/PTC1 rearrangement was preferentially induced in a dose-dependent manner by X-ra ys within a high dose range (10, 50 and 100 Gy) in four cell lines. On the other hand, RET/PTC3 was induced at a much lower frequency, and no inductio n of RET/PTC2 was observed. These results suggest that the preferential ind uction of the RET/PTC1 rearrangement may play an important role in the earl y steps of thyroid carcinogenesis induced by acute X-irradiation.