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

Abstract

Ionizing radiation is a well known risk factor of thyroid cancer development, but the mechanism of radiation induced carcinogenesis is not clear. The RET/PTC oncogene, an activated form of the RET proto-oncogene, is frequently observed in papillary thyroid carcinoma (PTC); RET/PTC1, -2 and -3 are known to be the three major forms. High frequencies of RET/PTC rearrangements have been observed in radiation-associated PTC, such as those appearing post-Chernobyl or post-radiotherapy, but the rearrangement types dier between these two populations. We investigated whether a speci®c type of RET/PTC rearrangement was induced by X-rays in vivo and in vitro. In human normal thyroid tissues transplanted in scid mice, the RET/PTC1 rearrangement was predominantly detected throughout the observation period (up to 60 days) after 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. These 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-rays 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 induction of RET/PTC2 was observed. These results suggest that the preferential induction of the RET/PTC1 rearrangement may play an important role in the early steps of thyroid carcinogenesis induced by acute X-irradiation. Oncogene (2000) 19, 438 ± 443.

H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization

“…Both thyroid and haematopoietic tissues are very sensitive to the effects of ionizing radiations (Ito et al, 1993;Bounacer et al, 1997a, b;Schlumberger et al, 1999;Mizuno et al, 2000;Rabes et al, 2000;Tuttle and Becker, 2000;Moysich The possible role exerted by the H4(D10S170) gene in carcinogenesis has been partially explored: it was reported that part of this gene product present in RET/PTC1 was responsible for the dimerization of the RET tyrosine kinase thus resulting in its constitutive activation (Tong et al, 1997). The mechanism of transformation for H4/PDGFRb has also been ascribed to constitutive activation of the receptor, which is dependent from portions of the H4(D10S170) coiledcoil domain contained in the oncogene (Schwaller et al, 2001).…”

The RET proto-oncogene in human cancers

“…While the incidence of RET/PTC activation in spontaneous PCs ranges from 5 ± 30% (Jhiang and Mazzaferri, 1994), the incidence of RET/PTC activation in radiation-induced PCs is in the range of 60 ± 70% (Klugbauer et al, 1995;Rabes et al, 2000). Indeed, it has been shown that RET/PTC activation can be induced by irradiation in cultured cells as well as in human thyroid tissues implanted in SCID mice (Mizuno et al, 2000). Moreover, RET/ PTC3 seems to be associated with PCs of solid variant and childhood PCs of short latency from areas contaminated by the Chernobyl nuclear reactor accident (Nikiforov et al, 1997;Thomas et al, 1999;Smida et al, 1999).…”

ret/PTC Activation Is Not Associated with Individual Radiation Dose Estimates in a Pilot Study of Neoplastic Thyroid Nodules Arising in Russian Children and Adults Exposed to Chernobyl Fallout

“…In cell culture models, a significant doseresponse relationship has been demonstrated using radiation doses similar to thyroid radiation dose estimates in children exposed to the Chernobyl fallout (12)(13)(14). However, Collins et al found that radiation dose to the thyroid from external beam irradiation of children for benign conditions was not significantly different between thyroid nodules that developed ret=PTC mutations (69 þ=À12 cGy) and those without ret=PTC mutations (89 þ=À29 cGy) (15).…”