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ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 2014 Mar 15;120(6):799-807

Date

12/12/2013

Pubmed ID

24327398

Pubmed Central ID

PMC3947712

DOI

10.1002/cncr.28484

Scopus ID

2-s2.0-84896723858   148 Citations

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.

Author List

Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, Nikiforov YE

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Base Sequence
Carcinoma, Papillary
Chernobyl Nuclear Accident
Environmental Exposure
Gene Fusion
Humans
Iodine Radioisotopes
Neoplasms, Radiation-Induced
Point Mutation
Proto-Oncogene Proteins c-ets
Receptor, trkC
Repressor Proteins
Sequence Analysis, RNA
Thyroid Neoplasms
Translocation, Genetic
Ukraine
United States
Young Adult
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d