Abstract 3599: Prevalance and spectrum of chromosomal rearrangements in post-Chernobyl thyroid cancer.
Authors: Leeman-Neill Rebecca J. , Brenner Alina J. , Little Mark P. , Bogdanova Tetiana , Hatch Maureen , Mabuchi Kiyohiko , Tronko Mykola , Nikiforov Yuri E. 
Published: August 2014

Abstract
Introduction: After the Chernobyl disaster, a strong association between childhood I-131 exposure and papillary thyroid carcinoma (PTC) was observed. Our previous study of PTCs from a Ukrainian cohort who were &lt; 18 y.o. at the time of Chernobyl and received 0.008-8.6 Gy of I-131 to the thyroid revealed that RET/PTC rearrangement was the most common mutation and correlated with I-131 dose (Cancer, in press). Common forms of rearrangement and point mutation were detected in 37 (60%) of these tumors. The aim of this study was to examine the remaining tumors for rare rearrangements known to occur in thyroid cancer and for novel chromosomal rearrangements.
Design: Twenty-five mutation-negative PTCs were analyzed. RT-PCR was used to search for BRAF/AKAP9 fusion and differential real-time PCR to search for all types of RET and NTRK1 rearrangements. After screening for these rearrangements, RNA from 12 tumors lacking all known mutation or rearrangement were used to create libraries and perform whole RNA sequencing on the Illumina HiSeq2000. Thyroid dose estimation was based on radioactivity measurements, environmental transport models, and interview data.
Results: Chromosomal rearrangements and point mutations identified in this cohort are shown, with patient characteristics, in Table 1. Additionally, through RNA-seq, a novel chromosomal rearrangement was identified in several tumors that lack known alteration and were associated with a mean thyroid dose of 2.39 Gy. This novel rearrangement is being validated and characterized.
Table 1. Chromosomal rearrangements and corresponding patient characteristics Genetic Alteration Mutation frequency I-131 dose, mean (Gy) Age at exposure, mean (yrs) Latency, mean (yrs) RET/PTC1 and 3 22 (36%) 1.22 6.4 15.9 Other RET/PTC 1 (1.6%) 0.01 11.5 14.2 PAX8/PPARγ 2 (3%) 0.62 12.2 13.5 BRAF/AKAP9 1 (1.6%) 0.27 11.2 20.8 NTRK1 rearrangement 1 (1.6%) 0.44 6.8 15.7 BRAF or RAS mutation 14 (22%) 0.27 10.5 17.6 None (or newly discovered) 22 (35%) 2.05 7.7 16.5 Overall 62 (100%) 1.27 8.1 16.5
Conclusions: Our results demonstrate the occurrence, although with low frequency, of NTRK1, BRAF/AKAP9, and rare types of RET/PTC rearrangements in this post-Chernobyl cohort. In addition, a novel chromosomal rearrangement was identified in tumors associated with high mean I-131 dose, which should further elucidate the genetic mechanisms of radiation-induced thyroid carcinogenesis.
Citation Format: Rebecca J. Leeman-Neill, Alina J. Brenner, Mark P. Little, Tetiana Bogdanova, Maureen Hatch, Kiyohiko Mabuchi, Mykola Tronko, Yuri E. Nikiforov. Prevalance and spectrum of chromosomal rearrangements in post-Chernobyl thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3599. doi:10.1158/1538-7445.AM2013-3599