ETV6-NTRK3 Is a Common Chromosomal Rearrangement in Radiation-Associated Thyroid Cancer

BACKGROUNDIn their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 (I-131) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors. METHODSIn 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. RESULTSThe 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 I-131 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 I-131 dose, albeit at borderline significance (P=.126). The group of rearrangement-positive PTCs (ETV6-NTRK3, RET/PTC, PAX8-PPAR) 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 I-131 and -radiation resulted in the formation of ETV6-NTRK3 rearrangement at a rate of 7.9x10(-6) cells and 3.0x10(-6) cells, respectively. CONCLUSIONSThe 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 I-131 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. (c) 2013 American Cancer Society. The occurrence of ETV6-NTRK3 rearrangements in thyroid cancer is analyzed, and the results indicate that these rearrangements are significantly more common in tumors associated with exposure to iodine-131. Moreover, the findings demonstrate that ETV6-NTRK3 rearrangements can be induced in thyroid cells by ionizing radiation in vitro, and this is likely to serve as a novel mechanism of radiation-induced carcinogenesis.