| Disease | Papillary thyroid carcinoma |
| Epidemiology | 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). RERF's 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). |
| Pathology | 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. |
| |  |
| |
| (A)Low magnification of papillary thyroid carcinoma with ACBD5/RET. (B)The larger magnification of solid/trabecular-like region. |
| |
| Hybrid Gene |
| |  |
| |
| A)The scheme of ACBD5, RET and ACBD5-RET gene, and predicted ACBD5-RET fusion cDNA as well as the cDNA sequence around the fusion point.Red and blue dotted boxes indicate tyrosine kinase domain and coiled-coil domain. (B)RT-PCR confirmation of ACBD5-RET fusion. Lanes 1, 2, and 6, PTC cases without rearranged RET; lanes 3, 5, and 7, those with RET/PTC1; lane 4, PTC harboring ACBD5-RET; lane 8, H2O for negative control; lane 9, cell line TPC1 harboring RET/PTC1; lane 10, the synthesized nucleotides for positive control of ACBD5-RET plus genomic DNA; lane M, DNA size marker(pUC19-MspI digest)(Hamatani et al., 2014). |
| |
| Transcript | 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. |
| Detection | : 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). |
| Fusion Protein |
| Description | 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. |
| Oncogenesis | 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). |
| | |
| Chernobyl-related thyroid cancer in children of Belarus: a case-control study |
| Astakhova LN, Anspaugh LR, Beebe GW, Bouville A, Drozdovitch VV, Garber V, Gavrilin YI, Khrouch VT, Kuvshinnikov AV, Kuzmenkov YN, Minenko VP, Moschik KV, Nalivko AS, Robbins J, Shemiakina EV, Shinkarev S, Tochitskaya SI, Waclawiw MA |
| Radiat Res 1998 Sep;150(3):349-56 |
| PMID 9728663 |
| |
| Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure |
| Furukawa K, Preston D, Funamoto S, Yonehara S, Ito M, Tokuoka S, Sugiyama H, Soda M, Ozasa K, Mabuchi K |
| Int J Cancer 2013 Mar 1;132(5):1222-6 |
| PMID 22847218 |
| |
| Mechanisms of chromosomal rearrangements in solid tumors: the model of papillary thyroid carcinoma |
| Gandhi M, Evdokimova V, Nikiforov YE |
| Mol Cell Endocrinol 2010 May 28;321(1):36-43 |
| PMID 19766698 |
| |
| Rearrangements of NTRK1 gene in papillary thyroid carcinoma |
| Greco A, Miranda C, Pierotti MA |
| Mol Cell Endocrinol 2010 May 28;321(1):44-9 |
| PMID 19883730 |
| |
| A novel RET rearrangement (ACBD5/RET) by pericentric inversion, inv(10)(p12 |
| Hamatani K, Eguchi H, Koyama K, Mukai M, Nakachi K, Kusunoki Y |
| 1;q11 2), in papillary thyroid cancer from an atomic bomb survivor exposed to high-dose radiation |
| PMID 25175022 |
| |
| Radiation dose-response relationships for thyroid nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors 55-58 years after radiation exposure |
| Imaizumi M, Usa T, Tominaga T, Neriishi K, Akahoshi M, Nakashima E, Ashizawa K, Hida A, Soda M, Fujiwara S, Yamada M, Ejima E, Yokoyama N, Okubo M, Sugino K, Suzuki G, Maeda R, Nagataki S, Eguchi K |
| JAMA 2006 Mar 1;295(9):1011-22 |
| PMID 16507802 |
| |
| Thyroid cancer after Chernobyl |
| Kazakov VS, Demidchik EP, Astakhova LN |
| Nature 1992 Sep 3;359(6390):21 |
| PMID 1522879 |
| |
| Prognostic utility of BRAF mutation in papillary thyroid cancer |
| Xing M |
| Mol Cell Endocrinol 2010 May 28;321(1):86-93 |
| PMID 19883729 |
| |
