title: Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation.
abstract: 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 gamma-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 gamma-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.
authors.affiliation: Department of Pathology, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670529, Cincinnati, Ohio 45267-0529, USA.
authors.forename: Christy M
authors.initials: CM
authors.lastname: Caudill
authors.forename: Zhaowen
authors.initials: Z
authors.lastname: Zhu
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ciampi
authors.forename: James R
authors.initials: JR
authors.lastname: Stringer
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D015321:Gene Rearrangement; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D013961:Thyroid Gland / Q000378:metabolism / Q000528:radiation effects*; D013964:Thyroid Neoplasms / Q000209:etiology* / Q000235:genetics
chemical_list: D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human