This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fugazzola, L. Articles by Pierotti, M. A. Search for Related Content PubMed PubMed Citation Articles by Fugazzola, L. Articles by Pierotti, M. A.

Oncogenic Rearrangements of the RET Proto-Oncogene in Papillary Thyroid Carcinomas from Children Exposed to the Chernobyl Nuclear Accident¹

Istituto di Endocrinologia, Universita' di Pisa, V.le del Tirreno 64, 56018 Tirrenia Pisa [L. F., A. P., F. P.]; Divisione di Anatomia Patologica e Citologia [S. P.] and Divisione di Oncologia Sperimentale A [P. M., I. B., A. G., M. G. B., M. A. P.], Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano, Italy; and Institute of Radiation Medicine [T. V. V., L. A.] and Oncology Center of Thyroid [E. P. D.], Minsk, Byelorussia

Since the Chernobyl nuclear reactor accident, a striking increase of thyroid carcinoma has been reported in children exposed to radiation in Belarus. Because of its unprecedented scale and its emotional implications, this finding has raised concern and called the attention of the scientific community to this major health problem. Although epidemiologically documented, a direct correlation between thyroid cancer and radiation exposure has not been definitely proven at the molecular level. On the assumption that ionizing radiation could cause specific and common cancer-associated genetic lesions, an analysis of oncogene activation and/or tumor suppressor gene inactivation would help to define radiation-induced thyroid carcinomas.

Therefore, we have analyzed by different molecular approaches, including Southern blotting, DNA transfection assay on NIH-3T3 cells, and reverse transcription-PCR analysis, six papillary carcinomas from children living in the region of Belarus at the time of the Chernobyl nuclear accident to identify tumor-specific gene rearrangements of the protooncogenes RET and TRK, previously found activated in a tumor type-specific manner in papillary thyroid carcinoma. Using Southern blot analysis in four cases, we could detect specific rearranged bands indicating an oncogenic activation of RET that in three cases resulted in rear-ranged sequences provided by the same activating gene. Moreover, the DNA of the last three cases showed a biological activity in transforming NIH-3T3 cells after the DNA-mediated transfection assay, and the respective NIH-3T3 transfectants were found to express the oncogenic fusion transcripts.

These results support the possibility that RET oncogenic activation could represent a major genetic lesion associated with thyroid carcinoma in children exposed to the Chernobyl nuclear accident.

¹ This work was supported by Consiglio Nazionale delle Ricerche "ACRO Project," Associazione Italiana Ricerche sul Cancro, and JSP4 EEC Chemobyl Projects COSU-CT93-0052.

² To whom requests for reprints should be addressed. Phone: 2-2390236; Fax: 2-2390764.

Received 9/19/95. Accepted 9/19/95.

This article has been cited by other articles:

				G. Riesco-Eizaguirre and P. Santisteban New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy Endocr. Relat. Cancer, December 1, 2007; 14(4): 957 - 977. [Abstract] [Full Text] [PDF]

				R. Ciampi and Y. E. Nikiforov RET/PTC Rearrangements and BRAF Mutations in Thyroid Tumorigenesis Endocrinology, March 1, 2007; 148(3): 936 - 941. [Abstract] [Full Text] [PDF]

				M. Santoro, R. M. Melillo, and A. Fusco RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur. J. Endocrinol., November 1, 2006; 155(5): 645 - 653. [Abstract] [Full Text] [PDF]

				Z. Zhu, R. Ciampi, M. N. Nikiforova, M. Gandhi, and Y. E. Nikiforov Prevalence of RET/PTC Rearrangements in Thyroid Papillary Carcinomas: Effects of the Detection Methods and Genetic Heterogeneity J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3603 - 3610. [Abstract] [Full Text] [PDF]

				M. Imaizumi, T. Usa, T. Tominaga, K. Neriishi, M. Akahoshi, E. Nakashima, K. Ashizawa, A. Hida, M. Soda, S. Fujiwara, et al. Radiation Dose-Response Relationships for Thyroid Nodules and Autoimmune Thyroid Diseases in Hiroshima and Nagasaki Atomic Bomb Survivors 55-58 Years After Radiation Exposure JAMA, March 1, 2006; 295(9): 1011 - 1022. [Abstract] [Full Text] [PDF]

				M Xing BRAF mutation in thyroid cancer Endocr. Relat. Cancer, June 1, 2005; 12(2): 245 - 262. [Abstract] [Full Text] [PDF]

				E Puxeddu, J A Knauf, M A Sartor, N Mitsutake, E P Smith, M Medvedovic, C R Tomlinson, S Moretti, and J A Fagin RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response Endocr. Relat. Cancer, June 1, 2005; 12(2): 319 - 334. [Abstract] [Full Text] [PDF]

				C. M. Caudill, Z. Zhu, R. Ciampi, J. R. Stringer, and Y. E. Nikiforov Dose-Dependent Generation of RET/PTC in Human Thyroid Cells after in Vitro Exposure to {gamma}-Radiation: A Model of Carcinogenic Chromosomal Rearrangement Induced by Ionizing Radiation J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2364 - 2369. [Abstract] [Full Text] [PDF]

				N. Mitsutake, J. A. Knauf, S. Mitsutake, C. Mesa Jr., L. Zhang, and J. A. Fagin Conditional BRAFV600E Expression Induces DNA Synthesis, Apoptosis, Dedifferentiation, and Chromosomal Instability in Thyroid PCCL3 Cells Cancer Res., March 15, 2005; 65(6): 2465 - 2473. [Abstract] [Full Text] [PDF]

				J Di Cristofaro, V Vasko, V Savchenko, S Cherenko, A Larin, M D Ringel, M Saji, M Marcy, J F Henry, P Carayon, et al. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients Endocr. Relat. Cancer, March 1, 2005; 12(1): 173 - 183. [Abstract] [Full Text] [PDF]

				S. Sadetzki, R. Calderon-Margalit, B. Modan, S. Srivastava, and R. M. Tuttle Ret/PTC Activation in Benign and Malignant Thyroid Tumors Arising in a Population Exposed to Low-Dose External-Beam Irradiation in Childhood J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2281 - 2289. [Abstract] [Full Text] [PDF]

				E. Puxeddu, S. Moretti, R. Elisei, C. Romei, R. Pascucci, M. Martinelli, C. Marino, N. Avenia, E. D. Rossi, G. Fadda, et al. BRAFV599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2414 - 2420. [Abstract] [Full Text] [PDF]

				M. Xing, V. Vasko, G. Tallini, A. Larin, G. Wu, R. Udelsman, M. D. Ringel, P. W. Ladenson, and D. Sidransky BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1365 - 1368. [Abstract] [Full Text] [PDF]

				E. Puxeddu, N. Mitsutake, J. A. Knauf, S. Moretti, H. W. Kim, K. A. Seta, D. Brockman, L. Myatt, D. E. Millhorn, and J. A. Fagin Microsomal Prostaglandin E2 Synthase-1 Is Induced by Conditional Expression of RET/PTC in Thyroid PCCL3 Cells through the Activation of the MEK-ERK Pathway J. Biol. Chem., December 26, 2003; 278(52): 52131 - 52138. [Abstract] [Full Text] [PDF]

				J. Wang, J. A. Knauf, S. Basu, E. Puxeddu, H. Kuroda, M. Santoro, A. Fusco, and J. A. Fagin Conditional Expression of RET/PTC Induces a Weak Oncogenic Drive in Thyroid PCCL3 Cells and Inhibits Thyrotropin Action at Multiple Levels Mol. Endocrinol., July 1, 2003; 17(7): 1425 - 1436. [Abstract] [Full Text] [PDF]

				E. T. Kimura, M. N. Nikiforova, Z. Zhu, J. A. Knauf, Y. E. Nikiforov, and J. A. Fagin High Prevalence of BRAF Mutations in Thyroid Cancer: Genetic Evidence for Constitutive Activation of the RET/PTC-RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma Cancer Res., April 1, 2003; 63(7): 1454 - 1457. [Abstract] [Full Text] [PDF]

				H.D. Lohrer, L. Hieber, and H. Zitzelsberger Differential mutation frequency in mitochondrial DNA from thyroid tumours Carcinogenesis, October 1, 2002; 23(10): 1577 - 1582. [Abstract] [Full Text] [PDF]

				B. J. Collins, G. Chiappetta, A. B. Schneider, M. Santoro, F. Pentimalli, L. Fogelfeld, T. Gierlowski, E. Shore-Freedman, G. Jaffe, and A. Fusco RET Expression in Papillary Thyroid Cancer from Patients Irradiated in Childhood for Benign Conditions J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3941 - 3946. [Abstract] [Full Text] [PDF]

				M. SANTORO, R. M. MELILLO, F. CARLOMAGNO, A. FUSCO, and G. VECCHIO Molecular Mechanisms of RET Activation in Human Cancer Ann. N.Y. Acad. Sci., June 1, 2002; 963(1): 116 - 121. [Abstract] [Full Text] [PDF]

				J. A. Fagin Perspective: Lessons Learned from Molecular Genetic Studies of Thyroid Cancer--Insights into Pathogenesis and Tumor-Specific Therapeutic Targets Endocrinology, June 1, 2002; 143(6): 2025 - 2028. [Full Text] [PDF]

				G. Chiappetta, P. Toti, F. Cetta, A. Giuliano, F. Pentimalli, I. Amendola, S. Lazzi, M. Monaco, L. Mazzuchelli, P. Tosi, et al. The RET/PTC Oncogene Is Frequently Activated in Oncocytic Thyroid Tumors (Hurthle Cell Adenomas and Carcinomas), but Not in Oncocytic Hyperplastic Lesions J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 364 - 369. [Abstract] [Full Text] [PDF]

				A. P. Heaney, V. Nelson, M. Fernando, and G. Horwitz Transforming Events in Thyroid Tumorigenesis and Their Association with Follicular Lesions J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 5025 - 5032. [Abstract] [Full Text] [PDF]

				R. Elisei, C. Romei, T. Vorontsova, B. Cosci, V. Veremeychik, E. Kuchinskaya, F. Basolo, E. P. Demidchik, P. Miccoli, A. Pinchera, et al. RET/PTC Rearrangements in Thyroid Nodules: Studies in Irradiated and Not Irradiated, Malignant and Benign Thyroid Lesions in Children and Adults J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3211 - 3216. [Abstract] [Full Text] [PDF]

				S. Klugbauer, A. Jauch, E. Lengfelder, E. Demidchik, and H. M. Rabes A Novel Type of RET Rearrangement (PTC8) in Childhood Papillary Thyroid Carcinomas and Characterization of the Involved Gene (RFG8) Cancer Res., December 1, 2000; 60(24): 7028 - 7032. [Abstract] [Full Text]

				M. N. Nikiforova, J. R. Stringer, R. Blough, M. Medvedovic, J. A. Fagin, and Y. E. Nikiforov Proximity of Chromosomal Loci That Participate in Radiation-Induced Rearrangements in Human Cells Science, October 6, 2000; 290(5489): 138 - 141. [Abstract] [Full Text]

				D. Salvatore, M. V. Barone, G. Salvatore, R. M. Melillo, G. Chiappetta, A. Mineo, G. Fenzi, G. Vecchio, A. Fusco, and M. Santoro Tyrosines 1015 and 1062 Are in VivoAutophosphorylation Sites in Ret and Ret-Derived Oncoproteins J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3898 - 3907. [Abstract] [Full Text]

				K. Salassidis, J. Bruch, H. Zitzelsberger, E. Lengfelder, A. M. Kellerer, and M. Bauchinger Translocation t(10;14)(q11.2;q22.1) Fusing the Kinectin to the RET Gene Creates a Novel Rearranged Form (PTC8) of the RET Proto-Oncogene in Radiation-induced Childhood Papillary Thyroid Carcinoma Cancer Res., June 1, 2000; 60(11): 2786 - 2789. [Abstract] [Full Text] [PDF]

				C. L. Fenton, Y. Lukes, D. Nicholson, C. A. Dinauer, G. L. Francis, and R. M. Tuttle The ret/PTC Mutations Are Common in Sporadic Papillary Thyroid Carcinoma of Children and Young Adults J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1170 - 1175. [Abstract] [Full Text]

				H. M. Rabes, E. P. Demidchik, J. D. Sidorow, E. Lengfelder, C. Beimfohr, D. Hoelzel, and S. Klugbauer Pattern of Radiation-induced RET and NTRK1 Rearrangements in 191 Post-Chernobyl Papillary Thyroid Carcinomas: Biological, Phenotypic, and Clinical Implications Clin. Cancer Res., March 1, 2000; 6(3): 1093 - 1103. [Abstract] [Full Text]

				G. A. Thomas, H. Bunnell, H. A. Cook, E. D. Williams, A. Nerovnya, E. D. Cherstvoy, N. D. Tronko, T. I. Bogdanova, G. Chiappetta, G. Viglietto, et al. High Prevalence of RET/PTC Rearrangements in Ukrainian and Belarussian Post-Chernobyl Thyroid Papillary Carcinomas: A Strong Correlation between RET/PTC3 and the Solid-Follicular Variant J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4232 - 4238. [Abstract] [Full Text]

				H. Zitzelsberger, L. Lehmann, L. Hieber, H.-U. G. Weier, C. Janish, J. Fung, T. Negele, F. Spelsberg, E. Lengfelder, E. P. Demidchik, et al. Cytogenetic Changes in Radiation-induced Tumors of the Thyroid Cancer Res., January 1, 1999; 59(1): 135 - 140. [Abstract] [Full Text] [PDF]

				D. L. Learoyd, M. Messina, J. Zedenius, A. I. Guinea, L. W. Delbridge, and B. G. Robinson RET/PTC and RET Tyrosine Kinase Expression in Adult Papillary Thyroid Carcinomas J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3631 - 3635. [Abstract] [Full Text]

				S.-C. J. Yeung, A. C. Chiu, R. Vassilopoulou-Sellin, and R. F. Gagel The Endocrine Effects of Nonhormonal Antineoplastic Therapy Endocr. Rev., April 1, 1998; 19(2): 144 - 172. [Abstract] [Full Text]

				M. J. Schlumberger Papillary and Follicular Thyroid Carcinoma N. Engl. J. Med., January 29, 1998; 338(5): 297 - 306. [Full Text] [PDF]

				Y. E. Nikiforov and J. A. Fagin Prevalence, Significance, and Biological Behavior of ret/PTC Associated Papillary Thyroid Carcinoma-- Author's Response J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 2016 - 2017. [Full Text] [PDF]

				F. Cetta, G. Montalto, M. Petracci, and A. Fusco Thyroid Cancer and the Chernobyl Accident. Are Long-Term and Long Distance Side Effects of FallOut Radiation Greater Than Estimated? J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 2015 - 2016. [Full Text] [PDF]

				F. Cetta Prevalence, Significance, and Biological Behavior of ret/PTC1 Associated Papillary Thyroid Carcinomac J. Clin. Endocrinol. Metab., May 1, 1997; 82(5): 1650 - 1650. [Full Text] [PDF]

				J. A. Fagin Familial Nonmedullary Thyroid Carcinoma--The Case for Genetic Susceptibility J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 342 - 344. [Full Text] [PDF]