A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas.

Papillary thyroid carcinomas have frequently been found to display oncogenic rearrangements of the NTRK1 gene, which encodes the high-affinity nerve growth factor receptor. Replacement of its extracellular domain by sequences coding for the 221 amino-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation in three of eight of these tumors. In all of them, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the splicing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kDa, which was constitutively phosphorylated on tyrosine. In two of the three tumors the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination, 5'TPM3-3'NTRK1 and 5'NTRK1-3'TPM3 sequences, respectively, and the previously demonstrated localization of both genes on the long arm of chromosome 1 lead us to suggest that an intrachromosomal inversion could be responsible for their recombination. In an attempt to understand the molecular basis that predisposes NTRK1 and TPM3 genes to be a recurrent target of illegitimate recombination, we have determined the nucleotide sequence around the breakpoints of the recombination products in all three patients as well as those of the corresponding regions from the normal TPM3 and NTRK1 genes. In these regions, a search for common features usually involved in illegitimate recombination in mammalian cells revealed the presence of some recombinogenic elements as well as pal-indromes, direct and inverted repeats, and Alu family sequences.