[Radiation-induced thyroid carcinomas in children: high prevalence of RET rearrangement]

Papillary thyroid carcinomas were observed in children living in the Gomel region of Belarus at the time of the Chernobyl reactor accident in April 1986. Radioactive fallout, iodine-131 in particular, led to thyroid doses of > 10 Gy in some cases. Till now, more than 400 thyroid carcinomas developed. They provide a unique possibility to search for characteristic molecular aberrations. Small fresh frozen thyroid tumor samples from 59 children were available. cDNA after reverse transcription of mRNA was amplified by multiplex PCR and analyzed for the presence of RET rearrangement (PTC1, 2 or 3) by identification-PCR with specific primers and by direct sequencing. A significantly higher prevalence of RET rearrangement was found in the thyroid carcinomas of radiation-exposed children than formerly described for adult thyroid carcinomas. While the prevailing type of RET rearrangement in adult thyroid carcinomas is PTC1 involving RET and the H4 gene, the majority of tumors in radiation-exposed children shows PTC3. In this type of rearrangement the 3'-tyrosin kinase domain of RET becomes dependent on the 5'-regulatory part of the ELE gene. Different breakpoints were found in the ELE gene. Besides ELE/RET transcripts, reciprocal RET/ELE transcripts were expressed indicating a complete inversion of the two genes after double stand break and their functional activity in both rearranged forms. Paracentric inversion on chromosome 10 bringing the functional tyrosine kinase domain of c-RET under the regulatory control of the ubiquitously expressed ELE gene appears to be a typical molecular lesion in thyroid carcinomas of children after radiation. This rearrangement is thought to endow juvenile thyrocytes with a clonal growth advantage and may be a critical initiating event of thyroid carcinogenesis in radiation-exposed children.