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ETV6-NTRK3 rearrangement may indicate radiation-induced thyroid cancer
The rearrangement of ETV6-NTRK3 in papillary thyroid cancer was significantly more common in tumors associated with exposure to iodine-131. In addition, ETV6-NTRK3 rearrangement can be directly induced by iodine-131 in vitro.
That finding suggests it may represent a novel molecular mechanism that contributes to the development of radiation-induced carcinogenesis.
Researchers evaluated data from a Ukrainian-American cohort of patients with papillary thyroid cancer who were exposed to iodine-131 during the Chernobyl nuclear accident in 1986.
The original cohort included 62 patients. Of them, 37 (60%) harbored RET/PTC rearrangements, as well as other mutations.
Researchers in the current study used RNA-sequencing and reverse transcriptase-polymerase chain reaction to evaluate the chromosomes from the remaining 25 patients who had mutation-negative tumors in the original analysis.
Two of these patients with sufficient RNA were selected for whole-transcriptome analysis.
One of these patients was aged 1 year at the time of the accident and received an estimated 7.5 Gy dose of iodine-131, which was among the highest observed in the cohort. The patient’s tumor demonstrated fusion between exon 4 of ETS variant gene 6 (ETV6) and exon 14 of the neurotrophin receptor 3 (NTRK3).
Overall, researchers observed nine cases of the ETV6-NTRK3 rearrangement among the entire cohort of 62 (14.5%).
Researchers detected the variation in three patients with sporadic papillary thyroid cancer among a cohort of 151 patients from the general US population (prevalence, 2%).
The crude prevalence of the ETV6-NTRK3 rearrangement was significantly higher in the post-Chernobyl cohort than in the general US cohort (P=.01) and remained significant after adjusting for age and sex (P=.019).
The prevalence of the ETV6-NTRK3 rearrangement also was associated with increasing dose of iodine-131; however, this association only reached borderline significance (P=.126).
After exposing in vitro cells to 1 Gy iodine-131, researchers observed ETV6-NTRK3 rearrangement at a rate of 7.9 x 10-6 cells vs. the 3 x 10-6 rate observed with 1 Gy gamma-radiation.
“We report for the first time the occurrence of the ETV6-NTRK3 chromosomal rearrangement in thyroid cancer, which was identified as common in the papillary thyroid cancers associated with iodine-131 exposure from the Chernobyl accident,” the researchers wrote. “Moreover, we demonstrate that this rearrangement can be directly induced by iodine-131 or gamma-radiation in vitro and, thus, may represent a novel molecular mechanism contributing to the development of radiation-induced thyroid cancer.”
Disclosure: The researchers report no relevant financial disclosures.
Perspective
Back to TopThe work by Leeman-Neill and colleagues defines a new potential oncogenic driver of radiation-induced thyroid cancers. Their comprehensive analysis is the first report of ETV6-NTRK3 translocations in papillary thyroid cancers. These alterations occur at higher rates in post-Chernobyl radiation-exposed patients. This work is important in that it further characterizes molecular events of interest in thyroid cancers, and especially in radiation-induced thyroid cancers. This may eventually result in the development of novel therapeutics for this disease. For instance, results from in vivo small-molecule kinase binding assays indicate that the ALK inhibitor crizotinib (Xalkori, Pfizer) was found to inhibit ETV6-NTRK3 kinase activity (Taipale M. Nat Biotechnol. 2013;31:630-637). Thus, these reports suggest intriguing future studies for radiation-induced papillary thyroid cancer.