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Enhanced Sensitivity of the RET Proto-Oncogene to Ionizing Radiation In vitro

¹ Institute of Genetic Medicine, European Academy, Bolzano, Italy; ² Genetics Cancer Susceptibility Unit and ³ Nutrition and Cancer Unit, IARC, Lyon, France; ⁴ European Center for the Validation of Alternative Methods, Institute for Health and Consumer Protection, JRC of the European Commission, Ispra, Italy; ⁵ Laboratoire des Lésions des Acides Nucléiques, CEA Grenoble, France; and ⁶ Unità di Genetica Medica, Dipartimento di Scienze Ginecologiche, Ostetriche, Pediatriche, Policlinico S. Orsola-Malpighi, Bologna, Italy

Requests for reprints: Giovanni Romeo, Dipartimento di Scienze Ginecologiche, Ostetriche, Pediatriche, Cattedra di Genetica Medica, Padiglione 11. Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy. Phone: 39-051-306474; Fax: 39-0516364004; E-mail: romeo{at}eurogene.org.

Key Words: ionizing radiation • papillary thyroid carcinoma • DNA damage • RET • COMET-FISH

Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker. [Cancer Res 2008;68(21):8986–92]

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