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Keywords:

  • thyroid cancer;
  • radiation;
  • chromosomal rearrangements;
  • NTRK3;
  • Chernobyl

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.