RET rearrangements in radiation-induced papillary thyroid carcinomas: Highprevalence of topoisomerase I sites at breakpoints and microhomology-mediated end joining in ELE1 and RET chimeric genes

Children exposed to radioactive iodine after the Chernobyl reactor accident frequently developed papillary thyroid carcinomas (PTC), The predominant m olecular lesions in these tumors are rearrangements of the RET receptor tyr osine kinase gene. Various types of RET rearrangements have been described. More than 90% of PTC with RET rearrangement exhibit a PTC1 or PTC3 type of rearrangement with an inversion of the H4 or ELE1 gene, respectively, on c hromosome 10, To obtain closer insight into the mechanisms underlying PTC3 inversions, we analyzed the genomic breakpoints of 22 reciprocal and 4 nonr eciprocal ELE1 and RET rearrangements in 26 post-Chernobyl tumor samples. I n contrast to previous assumptions, an accumulation of breakpoints at the t wo Alu elements in the ELE1 sequence was not observed. Instead, breakpoints are distributed in the affected introns of both genes without significant clustering. When compared to the corresponding wildtype sequences, the majo rity of breakpoints (92%) do not contain larger deletions or insertions. Mo st remarkably, at least one topoisomerase I site was found exactly at or in close vicinity to all breakpoints, indicating a potential role for this en zyme in the formation of DNA strand breaks and/or ELE1 and RET inversions. The presence of short regions of sequence homology (macrohomologies) and sh ort direct and inverted repeats at the majority of breakpoints furthermore indicates a nonhomologous DNA end-joining mechanism in the formation of chi meric ELE1/Ret and Ret/ELE1 genes, (C) 2001 Academic Press.