A SEQUENCE-ANALYSIS OF THE GENOMIC REGIONS INVOLVED IN THE REARRANGEMENTS BETWEEN TPM3 AND NTRK1 GENES PRODUCING TRK ONCOGENES IN PAPILLARYTHYROID CARCINOMAS

Papillary thyroid carcinomas have frequently been found to display onc ogenic rearrangements of the NTRK1 gene, which encodes the high-affini ty nerve growth factor receptor. Replacement of its extracellular doma in by sequences coding for the 221 amino-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation in three of e ight of these tumors. In all of them, the illegitimate recombination i nvolved the 611-bp NTRK1 intron placed upstream of the transmembrane d omain and the TPM3 intron located between exons 7 and 8. Therefore, du e to the splicing mechanism, all of the TPM3/NTRK1 gene fusions encode d an invariable transcript and the same chimeric protein of 70 kDa, wh ich was constitutively phosphorylated on tyrosine. In two of the three tumors the simultaneous presence of the reciprocal products of the TP M3/NTRK1 recombination, 5'TPIM3-3'NTRK1 and 5'NTRK1-3'TPM3 sequences, respectively, and the previously demonstrated localization of both gen es on the long arm of chromosome 1 lead us to suggest that an intrachr omosomal 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 c orresponding regions from the normal TPM3 and NTRK1 genes, In these re gions, a search for common features usually involved in illegitimate r ecombination in mammalian cells revealed the presence of some recombin ogenic elements as well as palindromes, direct and inverted repeats, a nd ALu family sequences. (C) 1995 Academic Press, Inc.