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¹ Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
² Department of Pathology, University of Michigan Medical School and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109-0054, USA
³ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
⁴ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

(Requests for offprints should be addressed to Y E Nikiforov who is now at Department of Pathology, University of Pittsburgh, A713 Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261, USA; Email: nikiforovye{at}upmc.edu)

R Ciampi is now at Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy

Chromosomal rearrangements of the RET proto-oncogene (RET/PTC) are the common feature of papillary thyroid carcinoma (PTC). In this study, we report the identification, cloning, and functional characterization of a novel type of RET/PTC rearrangement that results from the fusion of the 3'-portion of RET coding for the tyrosine kinase (TK) domain of the receptor to the 5'-portion of the Homo sapiens hook homolog 3 (HOOK3) gene. The novel fusion was identified in a case of PTC that revealed a gene expression signature characteristic of RET/PTC on DNA microarray analysis, but was negative for the most common types of RET rearrangement. A fusion product between exon 11 of HOOK3 and exon 12 of RET gene was identified by 5'RACE, and the presence of chimeric HOOK3-RET protein of 88 kDa was detected by western blot analysis with an anti-RET antibody. The protein is predicted to contain a portion of the coiled-coil domains of HOOK3 and the intact TK domain of RET. Expression of the HOOK3-RET cDNA in NIH3T3 cells resulted in the formation of transformed foci and in tumor formation after injection into nude mice, confirming the oncogenic nature of HOOK3-RET.