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.

Background: The Chornobyl accident in 1986 exposed thousands of people to radioactive iodine isotopes, particularly ¹³¹ I; this exposure was followed by a large increase in thyroid cancer among those exposed as children and adolescents, particularly in Belarus, the Russian Federation, and Ukraine. Here we report the results of the first cohort study of thyroid cancer among those exposed as children and adolescents following the Chornobyl accident. Methods: A cohort of 32 385 individuals younger than 18 years of age and resident in the most heavily contaminated areas in Ukraine at the time of the accident was invited to be screened for any thyroid pathology by ultrasound and palpation between 1998 and 2000; 13 127 individuals (44%) were actually screened. Individual estimates of radiation dose to the thyroid were available for all screenees based on radioactivity measurements made shortly after the accident and on interview data. The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model. Results: Forty-five pathologically confirmed cases of thyroid cancer were found during the 1998–2000 screening. Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate ( P <.001), yielding an estimated excess relative risk of 5.25 per Gy (95% confidence interval [CI] = 1.70 to 27.5). Greater age at exposure was associated with decreased risk of radiation-related thyroid cancer, although this interaction effect was not statistically significant. Conclusion: Exposure to radioactive iodine was strongly associated with increased risk of thyroid cancer among those exposed as children and adolescents. In the absence of Chornobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed, i.e., a reduction of 75% (95% CI = 50% to 93%). The study also provides quantitative risk estimates minimally confounded by any screening effects. Caution should be exercised in generalizing these results to any future similar accidents because of the potential differences in the nature of the radioactive iodines involved, the duration and temporal patterns of exposures, and the susceptibility of the exposed population.

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Genomics of radiation-induced damage: The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36-69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P = 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs.