ETV6‐NTRK3 is a common chromosomal rearrangement in radiation‐associated thyroid cancer. Issue 6 (10th December 2013)

• Record Type: Journal Article
• Authors: Leeman‐Neill, Rebecca J.; Kelly, Lindsey M.; Liu, Pengyuan; Brenner, Alina V.; Little, Mark P.; Bogdanova, Tetiana I.; Evdokimova, Viktoria N.; Hatch, Maureen; Zurnadzy, Liudmyla Y.; Nikiforova, Marina N.; Yue, Ning J.; Zhang, Miao; Mabuchi, Kiyohiko; Tronko, Mykola D.; Nikiforov, Yuri E.
• Is Part Of: Cancer. Volume 120:Issue 6(2014)
• Page Start: 799
• Page End: 807
• Publication Date: 2013-12-10
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.28484
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr28484-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian‐American cohort that was exposed to iodine‐131 (<sup>131</sup>I) from the Chernobyl accident, the authors identified <italic>RET/PTC</italic> rearrangements and other driver mutations in 60% of tumors.</p> </sec> <sec id="cncr28484-sec-0002" sec-type="section"> <title>METHODS</title> <p>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.</p> </sec> <sec id="cncr28484-sec-0003" sec-type="section"> <title>RESULTS</title> <p>The ETS variant gene 6 (<italic>ETV6</italic>)‐neurotrophin receptor 3 (<italic>NTRK3</italic>) rearrangement (<italic>ETV6</italic>‐<italic>NTRK3</italic>) was identified by RNA‐Seq in a tumor from a patient who received a high <sup>131</sup>I dose. Overall, the rearrangement was detected in 9 of 62 (14.5%) post‐Chernobyl PTCs and in 3 of 151 (2%) sporadic PTCs (<italic>P</italic> = .019). The most common fusion type was between exon 4 of <italic>ETV6</italic> and exon 14 of <italic>NTRK3</italic>. The prevalence of <italic>ETV6‐NTRK3</italic> rearrangement in post‐Chernobyl PTCs was associated with increasing <sup>131</sup>I dose, albeit at borderline significance (<italic>P</italic> = .126). The group of rearrangement‐positive PTCs (<italic>ETV6‐NTRK3</italic>, <italic>RET/PTC</italic>, <italic>PAX8‐PPARγ</italic>) was associated with significantly higher dose response compared with the group of PTCs with point mutations (<italic>BRAF</italic>, <italic>RAS</italic>; <italic>P</italic> < .001). In vitro exposure of human thyroid cells to 1 gray of <sup>131</sup>I and γ‐radiation resulted in the formation of <italic>ETV6‐NTRK3</italic> rearrangement at a rate of 7.9 × 10<sup>−6</sup> cells and 3.0 × 10<sup>−6</sup> cells, respectively.</p> </sec> <sec id="cncr28484-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>The authors report the occurrence of <italic>ETV6</italic>‐<italic>NTRK3</italic> rearrangements in thyroid cancer and demonstrate that this rearrangement is significantly more common in tumors associated with exposure to <sup>131</sup>I and has a borderline significant dose response. Moreover, <italic>ETV6‐NTRK3</italic> rearrangement can be directly induced in thyroid cells by ionizing radiation in vitro and, thus, may represent a novel mechanism of radiation‐induced carcinogenesis. <bold><italic>Cancer</italic> 2014;120:799–807</bold>. © <italic>2013 American Cancer Society</italic>.</p> </sec> </abstract>