Gene rearrangements in radiation-induced thyroid carcinogenesis

Background. Radiation is an accepted risk factor for thyroid carcinogenesis in children. Recent observations in large cohort of children and young adu lts who developed papillary thyroid carcinomas (PTC) related to accidental radiation exposure after the Chernobyl reactor accident revealed typical ge netic aberrations shedding light on genetic determinants and mechanisms of radiation-induced carcinogenesis. Procedure. A molecular genetic analysis w as performed on 191 post-Chernobyl PTC by RT-PCR, multiplex PCR, DNA sequen cing, and in some cases 5'RACE. Determination of point mutations was by mea ns of PCR and either allele-specific oligonucleotide hybridiziation or SSCP and DNA sequencing. Results, In various sporadic thyroid tumor types of ad ults structural genetic aberrations have been found involving mutations of RAS (codon 12, 13, 61), p53 (exons 5 to 8), Gs alpha (codon 201 and 227), a nd, at a low prevalence, the receptor tyrosine kinases RET or NTRK1. In con trast, in radiation-induced PTC of children RET rearrangements are by far t he most prevalent genetic aberrations. In these RET rearrangements, the tra nsmembrane and extracellular domains of RET are lost, and are replaced by p arts of other genes at the 5' end. These genes always contain coiled-coil d omains with dimerization potential and lead to constitutive, ligand-indepen dent activation of the ret tyrosine kinase domain at the 3' end of the fusi on product. The most frequent radiation-induced RET gene fusions involve th e ELE1 (ARA70) gene, a transcription coactivator of the androgen receptor ( PTC3), and H4, a gene of unknown function (PTC1). Both rearrangements origi nate from DNA double strand breaks with repair by intrachromosomal balanced paracentric inversion and recombination by illegitimate DNA endjoining at small stretches of homologous nucleotide sequences and direct or inverted r epeats, without significant breakpoint clusters in the involved introns. in addition, five different RET-fused genes, R1 alpha, GOLGA5, HTIF, RFG7 and RFG8, have been detected leading to the PTC2, 5, 6, 7 and 8 types of RET r earrangements, respectively. Each fusion leads, in principle, to the same e ffect: The ret tyrosine kinase is uncoupled from its stringent physiologica l regulation by replacement of its 5' end and is aberrantly activated by th e 5' parts of fused genes in thyrocytes that do not normally express ret ty rosine kinase. Ectopic ret expression, clonal expansion and early invasion are peculiar to the affected cells. The RET-fused gene is obviously decisiv e for modulating tumor development: ELE1/RET rearrangements lead to most ra pid tumor progression and are related to the solid variant of PTC, in contr ast to H4/RFT rearrangements connected with papillary or follicular Variant s of PTC. Conclusions. Typical genetic aberrations are produced by radioiod ine uptake in the juvenile thyroid gland. They act as determinants of pheno type, biology, and clinical course of radiation-induced papillary thyroid c arcinomas. Med. Pediatr. Oncol. 36:574-582, 2001. (C) 2001 Wiley-Liss, Inc.