Review
Rearrangements of NTRK1 gene in papillary thyroid carcinoma

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Abstract

TRK oncogenes are observed in a consistent fraction of papillary thyroid carcinoma (PTC); they arise from the fusion of the 3′ terminal sequences of the NTRK1/NGF receptor gene with 5′ terminal sequences of various activating genes, such as TPM3, TPR and TFG. TRK oncoproteins display constitutive tyrosine-kinase activity, leading to in vitro and in vivo transformation. In this review studies performed during the last 20 years will be summarized. The following topics will be illustrated: (a) frequency of TRK oncogenes and correlation with radiation and tumor histopathological features; (b) molecular mechanisms underlying NTRK1 oncogenic rearrangements; (c) molecular and biochemical characterization of TRK oncoproteins, and their mechanism of action; (d) role of activating sequences in the activation of TRK oncoproteins.

Section snippets

Molecular mechanisms underlying oncogenic NTRK1 rearrangements

Fig. 1 shows the chromosomal localization and transcriptional orientation of NTRK1 and its rearranging partners: TPM3, TPR on chromosome 1q, and TFG on chromosome 3q. The type of chromosomal rearrangement generating TRK oncogenes is not documented, since no cytogenetic studies on PTCs carrying NTRK1 rearrangements are available. A t(1;3)(q21;q11) translocation is most likely responsible for the generation of TRK-T3 oncogene (TFG/NTRK1 rearrangement). For TRK, TRK-T1 and TRK-T2, involving

NTRK1 receptor and TRK oncoproteins: structure and function

NTRK1, the high affinity receptor for NGF, is a member of the neurotrophin receptor family which also includes NTRK2 and NTRK3, binding to BDNF and NT3, respectively (Kaplan et al., 1991, Klein et al., 1991).

The NTRK1 receptor (Fig. 4) is a glycosylated protein of 140 kDa, comprising an extracellular portion, including Ig-like and leucine-rich domains for ligand binding, a single transmembrane domain, a juxta-membrane region, a tyrosine-kinase domain and a C-terminal tail. Following NGF binding,

Role of activating sequences in TRK oncogenic activation

The capability of TPM3, TPR and TFG to activate chimeric tyrosine-kinase oncogenes is not restricted TRK oncogenes; in fact, they have been found fused to other kinase genes. Both TPM3 and TFG were reported to fuse to ALK receptor gene in anaplastic large cell lymphoma (Hernandez et al., 2002, Lamant et al., 1999); moreover, TFG is rearranged with NOR1 in extraskeletal myxoid chondrosarcoma (Hisaoka et al., 2004). TPR was first identified in N-methyl-N′-nitro-N-nitrosoguanidine

Conclusions

Although occurring less frequently than RET rearrangements and BRAFV600E mutation, rearrangements of NTRK1 provide a useful model for studying the molecular basis of thyroid carcinogenesis. Studies performed almost exclusively in our laboratory have defined the mechanisms responsible for NTRK1 oncogenic rearrangements, and identified the molecular players involved in the process of TRK oncogenes transformation. Studies on TRK activating sequences have led to the identification of a novel gene,

Acknowledgements

This work is supported by AIRC (Associazione Italiana Ricerca Cancro), ACC (Alleanza Contro il Cancro), Ministry of Health. The Authors thanks Mrs. Cristina Mazzadi for secretarial help.

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