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Dose-Dependent Generation of RET/PTC in Human Thyroid Cells after in Vitro Exposure to -Radiation: A Model of Carcinogenic Chromosomal Rearrangement Induced by Ionizing Radiation

Departments of Pathology and Laboratory Medicine (C.M.C., Z.Z., R.C., Y.E.N.) and Molecular Genetics (J.R.S.), University of Cincinnati, Cincinnati, Ohio 45267-0529

Address all correspondence and requests for reprints to: Dr. Yuri Nikiforov, Department of Pathology, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670529, Cincinnati, Ohio 45267-0529. E-mail: Yuri.Nikiforov{at}uc.edu.

Ionizing radiation is a well-known risk factor for thyroid cancer in human populations. Chromosomal rearrangements involving the RET gene, known as RET/PTC, are prevalent in thyroid papillary carcinomas from patients with radiation history. We studied the generation of RET/PTC in HTori-3 immortalized human thyroid cells exposed to a range of doses of -radiation and harvested 2, 5–6, and 9 d later. RET/PTC1 and RET/PTC3 were detected by RT-PCR followed by Southern blotting and hybridization with internal oligonucleotide probes. No RET/PTC was found in cells harvested 2 and 5–6 d after irradiation, whereas 59 RET/PTC events were detected in cells collected 9 d after exposure. The average rate of RET/PTC induction was 0.1 x 10^–6 after exposure to 0.1 Gy, 1.6 x 10^–6 after 1 Gy, 3.0 x 10^–6 after 5 Gy, and 0.9 x 10^–6 after 10 Gy. When adjusted for cell survival, the rate after 10 Gy was comparable with those after 5 Gy. RET/PTC1 was more common than RET/PTC3 after each dose, comprising 80% of all rearrangements. In this study, we demonstrate a dose-dependent induction of RET/PTC rearrangements in human thyroid cells after exposure to 0.1–10 Gy -radiation. This provides additional evidence for a direct link between this genetic event and radiation exposure and offers a powerful experimental system for studying radiation-induced carcinogenesis in the thyroid gland.

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				Z. Zhu, R. Ciampi, M. N. Nikiforova, M. Gandhi, and Y. E. Nikiforov Prevalence of RET/PTC Rearrangements in Thyroid Papillary Carcinomas: Effects of the Detection Methods and Genetic Heterogeneity J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3603 - 3610. [Abstract] [Full Text] [PDF]