Characterization of a novel rearrangement from the ret/PTC family in a case of radiation-associated human thyroid papillary carcinoma

Abstract

In the tumor tissue of papillary thyroid carcinoma (PTC) developed in an externally irradiated patient, we identified an undescribed yet structural mutation which comprised the juxtapositioning of the 5′ portion of an rfp gene upstream of the fragment encoding the tyrosine kinase domain of RET. At the genomic level, the formation of a chimeric gene occurred as a result of balanced chromosomal translocation of the short arm of chromosome 6 and long arm of chromosome 10, t(6;10)(p21.3;q11.2). The presence of the mutation was confirmed by extensive molecular, cytogenetic, and functional analysis. The product of the fusion gene, termed Δrfp/RET, was able to form homodimers as demonstrated by a yeast two-hybrid system, thus being in compliance with an essential condition of the constitutive activation of ret/PTC tyrosine kinases. In addition, the newly revealed rearrangement was shown to be tumorigenic, as NIH 3T3 cells stably transfected with a mammalian expression vector encoding full-length cDNA of the Δrfp/RET yielded rapidly growing tumors in immunocompromised mice. The finding provides an additional line of evidence of facilitated susceptibility of the ret protooncogene to structural mutations in irradiated human thyroid cells and pathogenic role of the ret rearrangements in human papillary thyroid cancer.