Identification of a novel subtype of H4-RET rearrangement in a thyroid papillary carcinoma and lymph node metastasis

RET/PTC chimeric oncogenes are generated by the fusion of heterologous gene s to the RET tyrosine kinase encoding domain. These rearrangements are typi cal of papillary thyroid carcinomas. RET/PTC1 is one of the most frequently found RET/PTC version and, in all the cases so far reported, it is invaria bly generated by the fusion of the first encoding exon of the H4 gene to th e RET kinase encoding domain. This results in the generation of an oncogeni c protein containing the first 101 residues of the H4 protein at the N-term inus. We report the isolation of a novel subtype of H4-RET fusion, designat ed RET/PTC1L, from a human papillary carcinoma of the thyroid and lymph nod e metastasis. At variance with the classic one, this novel rearrangement ge nerates a protein containing the N-terminal 150 residues of H4. RET/PTC1L i s able to transform NIH 3T3 cells; its transforming ability, however, is 5- fold lower than that of the classic RET/PTC1 isoform. We propose that RET/P TC1L is a novel chimeric oncogene involved in thyroid tumorigenesis; its lo w transforming ability may be one of the reasons explaining the low frequen cy by which it is found in human thyroid carcinomas.