FREQUENT ACTIVATION OF RET PROTOONCOGENE BY FUSION WITH A NEW ACTIVATING GENE IN PAPILLARY THYROID CARCINOMAS

Tumor specific rearrangements of ret gene are frequently detected in p apillary thyroid carcinomas. These rearrangements result in the format ion of chimeric genes showing the tyrosine kinase domain of ret fused with the 5' end sequences of different genes. We examined a series of 52 patients and identified 10 cases of ret fusion with D10S170 locus r esulting in the generation of ret/PTC1 oncogene, 2 cases with the gene encoding the regulatory subunit RI alpha of PKA (ret/PTC2), and final ly 6 cases, here described, with a newly discovered gene called ele1 l ocalized on chromosome 10 and leading to the formation of ret/PTC3 onc ogene. Our results show the expression of the ret/PTC3 hybrid gene in all the 6 cases and demonstrated its association with the synthesis of 2 constitutively phosphorylated isoforms of the oncoprotein (p75 and p80). The chromosome 10 localization of both ret and ele1 and the dete ction, in all cases, of a sequence reciprocal to that generating the o ncogenic rearrangements, strongly suggest that ret/PTC3 formation is a consequence of an intrachromosomal inversion of chromosome 10.