| Hybrid Gene |
| Note | the RET/PTC1 oncogene, represents the first example of oncogene activation in solid tumors due to an acquired chromosomal abnormality |
| Description | RET/PTC1 is a chimeric transforming sequence generated by the fusion of the TK domain of RET to the 5' terminal sequence of the gene H4/D10S170; both partners in the fusion have been localized to chromosome 10q and their fusion is the molecular event consequent to a paracentromeric inversion of chromosome 10q, inv 10 (q11.2 q21.2) |
| Fusion Protein |
| Oncogenesis | H4/D10S170 has been shown to display a coiled-coil sequence which confers to the oncoprotein the ability to form dimers, resulting in a constitutive activation of the TK function |
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| Hybrid Gene |
| Note | a second example of RET activation is the RET/PTC2 oncogene; the cytogenetic analysis of one case of RET/PTC2 positive carcinoma revealed that this oncogene arises from a t(10;17)(q11.2;q23) reciprocal translocation |
| Description | in this case the rearrangement involved the gene of the regulatory subunit RI-a of Protein Kinase A, which maps to chromosome 17q23 |
| Fusion Protein |
| Oncogenesis | interestingly, like the H4 gene, RI-a also contains a dimerization domain and the construction of RET/PTC2 mutants with deletions in RI-a, has demonstrated that the formation of dimers is necessary to express the activity of the oncogene |
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| Hybrid Gene |
| Note | finally, a third example of RET activation in PTCs has been reported, RET/PTC3; also in this case, a paracentric inversion of the long arm of chromosome 10 was identified |
| Fusion Protein |
| Oncogenesis | In this oncogene, the TK domain of RET is fused to sequences derived from a previously unknown gene named ELE1 (otherwise named RFG). ELE1 is localized in the same chromosomal region of RET, 10q11.2 |
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| Hybrid Gene |
| Note | several cases of PTCs showed an activation of the NTRK1 proto-oncogene; in three specimens a chimeric sequence generated by the rearrangement of an isoform of non-muscle tropomyosin (TPM3) and NTRK1 was identified; the former has been mapped to chromosome 1q22-23; therefore, the NTRK1 localization on 1q22 suggested that a 1q intrachromosomal rearrangement could have generated the TRK oncogene |
| Description | molecular analysis of TRK positive PTCs revealed the presence, not only of the product of the oncogenic rearrangement (5'TPM3-3'NTRK1), but also of that related to the reciprocal event (5'NTRK1-3'TPM3); this finding indicates that an intrachromosomal inversion, inv(1q), provided the mechanism of the NTRK1 oncogenic activation in these tumors. |
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| Hybrid Gene |
| Note | in the remaining cases genes different from TPM provided the 5' terminus of the oncogene; therefore the latter were designated as TRK-T. three cases showed the fusion of NTRK1-TK domain to sequences of the TPR (Translocated Promoter Region) gene, originally identified as part of the MET oncogene |
| Description | the first of these cases, TRK-T1, is encoded by a hybrid mRNA containing 598 nucleotides of TPR and 1148 nucleotides of NTRK1; the TPR locus is on chromosome 1q25; therefore, as for TRK, an intrachromosomal rearrangement, molecularly defined as an inversion of 1q, is responsible for its formation; a rearrangement involving the same two genes, TPR and NTRK1, has been found in two other papillary thyroid tumors; although the two rearrangements involve different genomic regions of the partner genes, they occur in the same intron of both TPR and NTRK1; as a consequence, the same mRNA and 1323 aminoacid oncoprotein are produced and designated TRK-T2 in both cases; similarly to TRK-T1, the molecular characterization of these rearrangements indicated the chromosomal mechanism leading to the oncogenic activation as an inv(1q) |
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| Hybrid Gene |
| Note | as for the last two oncogenes derived from NTRK1 activation, one is still uncharacterized whereas the other, designated TRK-T3, has recently been analyzed. |
| Description | sequence analysis revealed that TRK-T3 contains 1412 nucleotides of NTRK1 preceded by 598 nucleotides belonging to a novel gene named TFG (TRK Fused Gene) encoding a 68 kDa cytoplasmic protein; the latter displays, in the TFG part, a coiled-coil region that endows the oncoprotein with the capability to form complexes, as shown by the TK domains; in this condition, the latter can recruit SH2 and SH3 containing cytoplasmic effector proteins |
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