Intrachromosomal rearrangement

Papillary Thyroid Carcinoma is a malignant tumor with papillary sturucture derived from thyroid follicular epithelial cells. The tumor cells show cytological features including overlapping nuclei, nuclear grooves and intranuclear cytoplasmic inclusions.

Thyroid cancer is one of the malignancies most closely associated with exposure to ionizing radiation in humans, such as exposure produced by the atomic bombings in Hiroshima and Nagasaki (Imaizumi et al., 2006) and by the Chernobyl nuclear power plant accident (Kazakov et al., 1992; Astakhova et al., 1998). RERFs statisticians have recently reported that about 36% of the PTC cases among those exposed as children or adolescents (below 20 years old) were estimated to be attributable to radiation exposure, which was considerably higher than that of 4% for those exposed as adults (above 20 years old) (Furukawa et al., 2013). Constitutive activation of the mitogen-activated protein kinase (MAPK)-signaling pathway-such as alterations of RET, NTRK1, BRAF, and RAS genes-are frequently found in PTC (Gandhi et al., 2010; Greco et al., 2010; Xing et al., 2010). These gene alterations can be detected in more than 70% of PTC cases. In PTC from A-bomb survivors who were exposed to a radiation dose of more than 500 mGy, gene rearangements, including RET, NTRK1 and ALK genes, were frequently detected (Hamatani et al., 2008 and 2012).

This PTC case developed from one A-bomb survivor exposed to radiation dose of 1.8 Gy showed moderately or well differentiated papillary structure with solid/trabecular-like architectures in several areas within cancerous regions.

ACBD5 (acyl-CoA binding domain containing 5)

10p12.1

ACBD5 (acyl-coenzyme A binding domain containing 5)is a member of the acyl-Coenzyme A binding protein family, known to function in the transport and distribution of long chain acyl-Coenzyme A. This gene may play a role in the differentiation of megakaryocytes and formation of platelets. Seven spliced variants have been reported (RefSeq, July 2014).

RET (REarranged during Transfection)

10q11.21

RET is a tyrosine kinase receptor whose ligands are neurotrophic factors of the glial-cell line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin and persefin. RET activation is mediated via different glycosyl phosphatidylinositol-linked GRF-receptors (Niccoli-Sire http://documents.irevues.inist.fr/bitstream/handle/2042/38039/10-2003-RETID76.pdf ).

ACBD5-RET fusion traanscript was detected in an exposed PTC case. Exon 1-12 of ACBD5 gene located on 10p12.1 is fused to exon 12-20 of RET gene located 10q11.2 by pericentric inversion of chromosome 10.

: A 102 bp cDNA fragment of ACBD5-RET containing the fusion point was detected by SMART RACE method with SMART adaptor-specific primer (5-AAGCAGTGGTAACAACGCAGAGTA-3) and RET gene-specific reverse primer (5-TCCGAGGGAATTCCCACTTT-3)(Hamatani et al., 2010).

This fusion protein contains the tyrosine kinase domain of RET and coiled-coil domain of ACBD5 even if any variant of ACBD5 is fused to RET, since coiled-coil domain of ACBD5 gene is located on exon 10.

Tumorigenicity of ACBD5-RET fusion gene was indicated by an in vitro kinase assay and a in vivo tumorigenesis assay with nude mice (Hamatani et al., 2014). The tumorigenesis induced by ACBD5-RET fusion gene products would be due to the constitutive activation of tyrosine kinase of RET gene through the homodimerization of this fusion gene followed by the constitutive activation of MAPK pathway (Hamatani et al., 2014).