Gene rearrangements in thyroid carcinomas after irradiation during childhood: lessons from the Chernobyl reactor accident

Abstract

Papillary thyroid carcinomas (PTC) developed with a high incidence in children and young adults who had been exposed to radioactive fallout in contaminated regions of Belarus after the Chernobyl reactor accident. They are informative for a molecular genetic analysis of radiation-induced PTC. In contrast to spontaneous PTC, a high prevalence of gene aberrations was found with rearrangements of the receptor tyrosine kinase gene RET in the majority of cases and a few NTRK1 rearrangements. In the rearranged form of RET, the transmembrane and extracellular parts are replaced by regulatory units of other genes. Among the fused genes, ELE1 ( ARA70) is most prevalent in PTC at short latency periods after irradiation, H4 gene fusions prevail in later-occurring PTC. Both types of rearrangement, PTC3 and PTC1, respectively, are formed by intrachromosomal inversions on chromosome 10. Analysing ELE1/ RET chimeric genes, we found radiation-induced DNA breakpoints localized exactly at or in close vicinity to topoisomerase I binding sites indicating a role for this enzyme in the formation of DNA breaks after irradiation. Breakpoints are distributed in the affected introns of both genes without significant clustering. They do not contain larger deletions of insertions. Short regions of sequence homology and short direct or inverted repeats were observed at the breakpoints suggesting microhomology-mediated DNA end joining as a mechanism in the fusion process. In addition to PTC1 and PTC3, we and others described several rare novel types of RET rearrangement, all formed by interchromosomal translocations, with parts of RIα, GOLGA5, HTIF, RFG7, RFG8, KTN1, and ELKS fused at the 5' end of the RET tyrosine kinase domain. These gene fusions appear to have in common an uncoupling of the RET tyrosine kinase from its physiological control due to an inherent dimerization potential. This may lead to constitutive, ligand-independent activation of RET tyrosine kinase in thyrocytes lacking this activity under normal conditions, and subsequent clonal expansion of the affected cells. It is evident from our comparative study on a large number of PTC with ELE1/ RET and H4/ RET rearrangements after irradiation that the type of the RET-fused gene determines the tumor phenotype and may be decisive also for the clinical course of radiation-induced PTC.