title: ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.
abstract: BACKGROUND
  In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 ((131) I) 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 (131) I 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 (131) I 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 (131) I 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 (131) I 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.
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors: Rebecca J
authors: RJ
authors: Leeman-Neill
authors: Lindsey M
authors: LM
authors: Kelly
authors: Pengyuan
authors: P
authors: Liu
authors: Alina V
authors: AV
authors: Brenner
authors: Mark P
authors: MP
authors: Little
authors: Tetiana I
authors: TI
authors: Bogdanova
authors: Viktoria N
authors: VN
authors: Evdokimova
authors: Maureen
authors: M
authors: Hatch
authors: Liudmyla Y
authors: LY
authors: Zurnadzy
authors: Marina N
authors: MN
authors: Nikiforova
authors: Ning J
authors: NJ
authors: Yue
authors: Miao
authors: M
authors: Zhang
authors: Kiyohiko
authors: K
authors: Mabuchi
authors: Mykola D
authors: MD
authors: Tronko
authors: Yuri E
authors: YE
authors: Nikiforov
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002291:Carcinoma, Papillary / Q000208:ethnology / Q000235:genetics*; D047852:Chernobyl Nuclear Accident; D004781:Environmental Exposure / Q000009:adverse effects; D050939:Gene Fusion; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects; D009381:Neoplasms, Radiation-Induced / Q000208:ethnology / Q000235:genetics*; D017354:Point Mutation; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D020812:Receptor, trkC / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D013964:Thyroid Neoplasms / Q000208:ethnology / Q000235:genetics*; D014178:Translocation, Genetic; D014455:Ukraine / Q000208:ethnology; D014481:United States / Q000453:epidemiology; D055815:Young Adult; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D007457:Iodine Radioisotopes; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein
keywords: Chernobyl; NTRK3; chromosomal rearrangements; radiation; thyroid cancer