The first two authors contributed equally to this article.
ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer
Article first published online: 10 DEC 2013
© 2013 American Cancer Society
Volume 120, Issue 6, pages 799–807, 15 March 2014
How to Cite
Leeman-Neill, R. J., Kelly, L. M., Liu, P., Brenner, A. V., Little, M. P., Bogdanova, T. I., Evdokimova, V. N., Hatch, M., Zurnadzy, L. Y., Nikiforova, M. N., Yue, N. J., Zhang, M., Mabuchi, K., Tronko, M. D. and Nikiforov, Y. E. (2014), ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer, 120: 799–807. doi: 10.1002/cncr.28484
We thank the staff of the University of Pittsburgh Health Sciences Tissue Bank for providing samples of sporadic thyroid tumors used in this study. We are grateful to Dr. Geraldine Thomas (Imperial College, London, UK) for her valuable assistance and support of the study. We also gratefully acknowledge the confirmation of diagnoses provided by the International Pathology Panel of the Chernobyl Tissue Bank; and we are also grateful to our dosimetry colleagues, including Drs. I. A. Likhtarev, L. N. Kovgan, A. Bouville, and V. Drozdovitch, for their valuable contributions to iodine-I thyroid dose estimates.
- Issue published online: 4 MAR 2014
- Article first published online: 10 DEC 2013
- Manuscript Accepted: 8 OCT 2013
- Manuscript Revised: 7 OCT 2013
- Manuscript Received: 4 SEP 2013
- thyroid cancer;
- chromosomal rearrangements;
In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 (131I) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors.
In this study, the remaining mutation-negative tumors from that cohort were analyzed using RNA sequencing (RNA-Seq) and reverse transcriptase-polymerase chain reaction to identify novel chromosomal rearrangements and to characterize their relation with radiation dose.
The ETS variant gene 6 (ETV6)-neurotrophin receptor 3 (NTRK3) rearrangement (ETV6-NTRK3) was identified by RNA-Seq in a tumor from a patient who received a high 131I dose. Overall, the rearrangement was detected in 9 of 62 (14.5%) post-Chernobyl PTCs and in 3 of 151 (2%) sporadic PTCs (P = .019). The most common fusion type was between exon 4 of ETV6 and exon 14 of NTRK3. The prevalence of ETV6-NTRK3 rearrangement in post-Chernobyl PTCs was associated with increasing 131I dose, albeit at borderline significance (P = .126). The group of rearrangement-positive PTCs (ETV6-NTRK3, RET/PTC, PAX8-PPARγ) was associated with significantly higher dose response compared with the group of PTCs with point mutations (BRAF, RAS; P < .001). In vitro exposure of human thyroid cells to 1 gray of 131I and γ-radiation resulted in the formation of ETV6-NTRK3 rearrangement at a rate of 7.9 × 10−6 cells and 3.0 × 10−6 cells, respectively.
The authors report the occurrence of ETV6-NTRK3 rearrangements in thyroid cancer and demonstrate that this rearrangement is significantly more common in tumors associated with exposure to 131I and has a borderline significant dose response. Moreover, ETV6-NTRK3 rearrangement can be directly induced in thyroid cells by ionizing radiation in vitro and, thus, may represent a novel mechanism of radiation-induced carcinogenesis. Cancer 2014;120:799–807. © 2013 American Cancer Society.