Abstract
The RET/PTC3 rearrangement is formed by fusion of the ELE1 and RET genes, and is highly prevalent in radiation-induced post-Chernobyl papillary thyroid carcinomas. We characterized the breakpoints in the ELE1 and RET genes in 12 post-Chernobyl pediatric papillary carcinomas with known RET/PTC3 rearrangement. We found that the breakpoints within each intron were distributed in a relatively random fashion, except for clustering in the Alu regions of ELE1. None of the breakpoints occurred at the same base or within a similar sequence. There was also no evidence of preferential cleavage in AT-rich regions or other target DNA sites implicated in illegitimate recombination in mammalian cells. Modification of sequences at the cleavage sites was minimal, typically involving a 1 – 3 nucleotide deletion and/or duplication. Surprisingly, the alignment of ELE1 and RET introns in opposite orientation revealed that in each tumor the position of the break in one gene corresponded to the position of the break in the other gene. This tendency suggests that the two genes may lie next to each other but point in opposite directions in the nucleus. Such a structure would facilitate formation of RET/PTC3 rearrangements because a single radiation track could produce concerted breaks in both genes, leading to inversion due to reciprocal exchange via end-joining.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bongarzone I, Butti MG, Fugazzola L, Pacini F, Pinchera A, Vorontsova TV, Demidchik EP and Pierotti MA. . 1997 Genomics 42: 252–259.
Bongarzone I, Fugazzola L, Vigneri P, Mariani L, Mondellini P, Pacini F, Basolo F, Pinchera A, Pilotti S and Pierotti MA. . 1996 J. Clin. Endocrinol. Metab. 81: 2006–2009.
Cremer C, Münkel C, Granzow M, Jauch A, Dietzel S, Eils R, Guan X-Y, Meltzer PS, Trent JM, Langowski J and Cremer T. . 1996 Mutat. Res. 366: 97–116.
Ehrlich SD, Bierne H, d'Alencon E, Vilette D, Petranovic M, Noirot P and Michel B. . 1993 Gene 135: 161–166.
Ferguson M and Ward DC. . 1992 Chromosoma 101: 557–565.
Fugazzola L, Pilotti S, Pinchera A, Vorontsova TV, Mondellini P, Bongarzone I, Greco A, Astakhova L, Butti MG, Demidchik EP, Pacini F and Pierotti MA. . 1995 Cancer Res. 55: 5617–5620.
Gerdes MG, Carter KC, Moen PT and Lawrence JB. . 1994 J. Cell Biol. 126: 289–304.
Grosovsky AJ, de Boer JG, deJong PJ, Drobetsky EA and Glickman BW. . 1988 Proc. Natl. Acad. Sci. USA. 85: 185–188.
Hyrien O, Debatisse M, Buttin G and de Saint Vinsent BR. . 1987 EMBO J. 6: 2401–2408.
Kazakov VS, Demidchik EP and Astakhova LN. . 1992 Nature 359: 21.
Klugbauer S, Lengfelder E, Demidchik EP and Rabes HM. . 1995 Oncogene 11: 2459–2461.
Kovacs MS, Evans JW, Johnstone IM and Brown JM. . 1994 Radiat. Res. 137: 34–43.
Lichter P, Cremer T, Borden J, Manuelidis L and Ward DC. . 1988 Hum. Genet. 80: 222–224.
Manuelidis L. . 1984 Proc. Natl. Acad. Sci. USA 81: 3123–3127.
Minoletti F, Butti MG, Coronelli S, Miozzo M, Sozzi G, Pilotti S, Tunnacliffe A, Pierotti MA and Bongarzone I. . 1994 Genes Chrom. Cancer 11: 51–57.
Mizuno T, Kyoizumi S, Suzuki T, Iwamoto KS and Seyama T. . 1997 Oncogene 15: 1455–1460.
Nikiforov YE and Gnepp DR. . 1994 Cancer 74: 748–766.
Nikiforov YE, Nikiforova M, Gnepp DR and Fagin JA. . 1996 Oncogene 13: 687–693.
Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H and Fagin JA. . 1997 Cancer Res. 57: 1690–1694.
Nikiforov YE and Fagin JA. . 1998 In: Advances in Molecular and Cellular Endocrinology. Vol 2, LeRoith D. (ed.). JAI Press Inc: Greenwich, Connecticut pp. 169–196.
Pacini F, Vorontsova T, Demidchik E, Molinaro E, Agate L, Romei C, Shavrova E, Cherstvoy E, Ivashkevitch Y, Kuchinskaya E, Schlumberger M, Rouga G, Felesi M and Pinchera A. . 1997 J. Clin. Endocrinol. Metab. 82: 3563–3569.
Pinkel D, Landegent J, Collins C, Fuscoe J, Seagraves R, Lucas J, Gray JW. . 1998 Proc. Natl. Acad. Sci. USA 85: 9138–9142.
Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G and Fusco A. . 1994 Oncogene 9: 509–516.
Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G and Fusco A. . 1993 Cell Growth Differen. 4: 77–84.
Stary A and Sarasin A. . 1992 Nucleic Acids Res. 20: 4269–4274.
Suchy B, Waldmann V, Klugbauer S and Rabes HM. . 1998 Br. J. Cancer 77: 952–955.
Ward JF . 1988 Progr. Nucleic Acids Mol. Biol. 35: 95–125.
Yokota H, van den Engh G, Hearst JE, Sachs RK and Trask BJ. . 1995 J. Cell Biol. 130: 1239–1249.
Acknowledgements
This work was supported by a TRAC award from Knoll Pharmaceuticals to Dr Nikiforov and in parts by grants CA 50706, CA 72597 to Dr Fagin and ES 05652 to Dr Stringer. We are grateful to Dr Fenoglio-Preiser for valuable comments.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nikiforov, Y., Koshoffer, A., Nikiforova, M. et al. Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas. Oncogene 18, 6330–6334 (1999). https://doi.org/10.1038/sj.onc.1203019
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203019
Keywords
This article is cited by
-
Genetic alterations landscape in paediatric thyroid tumours and/or differentiated thyroid cancer: Systematic review
Reviews in Endocrine and Metabolic Disorders (2024)
-
Age-related long-term response in rat thyroid tissue and plasma after internal low dose exposure to 131I
Scientific Reports (2022)
-
Clinical features may help to identify children and adolescents with greatest risk for thyroid nodules
Journal of Endocrinological Investigation (2020)
-
Values of molecular markers in the differential diagnosis of thyroid abnormalities
Journal of Cancer Research and Clinical Oncology (2017)
-
The biogenesis of chromosome translocations
Nature Cell Biology (2014)