ONCOGENIC REARRANGEMENTS OF THE RET PROTOONCOGENE IN PUPILLARY THYROID CARCINOMAS FROM CHILDREN EXPOSED TO THE CHERNOBYL NUCLEAR ACCIDENT

Since the Chernobyl nuclear reactor accident, a striking increase of t hyroid carcinoma has been reported in children exposed to radiation in Belarus. Because of its unprecedented scale and its emotional implica tions, this finding has raised concern and called the attention of the scientific community to this major health problem. Although epidemiol ogically documented, a direct correlation between thyroid cancer and r adiation exposure has not been definitely proven at the molecular leve l. On the assumption that ionizing radiation could cause specific and common cancer-associated genetic lesions, an analysis of oncogene acti vation and/or tumor suppressor gene inactivation would help to define radiation-induced thyroid carcinomas. Therefore, we have analyzed by d ifferent molecular approaches, including Southern blotting, DNA transf ection assay on NIH-3T3 cells, and reverse transcription-PCR analysis, six papillary carcinomas from children living in the region of Belaru s at the time of the Chernobyl nuclear accident to identify tumor-spec ific gene rearrangements of the protooncogenes RET and TRK, previously found activated in a tumor type-specific manner in papillary thyroid carcinoma. Using Southern blot analysis in four casts, we could detect specific rearranged bands indicating an oncogenic activation of RET t hat in three cases resulted in rearranged sequences provided by the sa me activating gene. Moreover, the DNA of the last three cases showed a biological activity in transforming NIH-3T3 cells after the DNA-media ted transfection assay, and the respective NIH-3T3 transfectants were found to express the oncogenic fusion transcripts. These results suppo rt the possibility that RET oncogenic activation could represent a maj or genetic lesion associated with thyroid carcinoma in children expose d to the Chernobyl nuclear accident.