A major health effect of the 1986 Chernobyl nuclear power plant accident is the increase in incidence of thyroid cancer, particularly among those exposed to radioactive fallout as children or adolescents. Studies of this population, carried out by REB and the Institute of Endocrinology and Metabolism in Ukraine, have found a strong, linear relationship between individual I-131 thyroid dose and risk of thyroid cancer that remains elevated two decades after exposure (Brenner et al., 2011). The investigators estimate that half of incident cancers in the cohort could be attributed to I-131 exposure. A parallel study in Belarus found a similarly strong association for prevalent thyroid cancers (Zablotska et al., 2011).
To date, the molecular signatures as well as the mechanisms underlying this association remain poorly understood. Jointly with colleagues at IEM, Bundeswehr Institute of Radiobiology, and University of Pittsburgh, we recently conducted studies of mRNA expression and targeted somatic alterations using DNA and RNA aliquots extracted from tumor/normal pairs drawn from 62 Ukrainian cases received through the Chernobyl Tissue Bank (CTB) (Abend et al., 2012; Abend et al., 2013; Leeman-Neill et al., 2013; Leeman-Neill et al., 2014). For the first time, we were able to link altered gene expression with individual I-131 doses; we identified and validated 11 genes with evidence of differential (tumor/normal tissue) dose-expression (Abend et al., 2012), and an additional eight genes in tumor tissue and six genes in normal tissue exhibiting dose-expression associations (Abend et al., 2013). We further evaluated dose-response relationship for known somatic alterations that may occur in sporadic and radiation-related thyroid cancer (BRAF, RAS point mutations and RET/PTC, PAX8/PPARG rearrangements). We reported a significant inverse association between I-131 dose and either BRAF or RAS point mutations as well as a significant concave association with I-131 dose for RET/PTC and PAX8/PPARG chromosomal rearrangements (Leeman-Neill et al., 2013). In an early pilot study of RNA-seq analysis in two UkrAm cases, we identified an additional rearrangement, an ETV6-NTRK3 fusion that was then confirmed by qRT-PCR to be present in 15% of all cases (Leeman-Neill et al., 2014).
Following up on these focused genetic studies, REB researchers are conducting a large-scale study of comprehensive genomic characterization of radiation-related PTCs using a combination of biological samples and information on radiation exposure, clinical, and demographic characteristics from the CTB. The primary objective of the study is to evaluate genomic, transcriptomic, and epigenomic landscapes of 450 radiation-related PTCs using the whole genome sequencing technologies and to compare these with sporadic, unrelated to radiation exposure PTCs (500 TCGA and 50 CTB cases from the Ukraine) and across different levels of I-131 exposure. The study has the potential to provide unique insights into the mechanisms of radiation carcinogenesis and to generate a rich data resource.
For more information, contact Kiyohiko Mabuchi.
Brenner AV, Tronko MD, Hatch M, et al. I-131 dose-response for incident thyroid cancers related to the Chornobyl accident in Ukraine. Environ Health Perspect 2011;119:933-939.
Zablotska LB, Ron E, Rozhko AV, et al. Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident. BJC 2011;104:181-187.
Abend M, Pfeiffer RM, Ruf C, et al. Dose dependent gene expression in thyroid cancer and corresponding normal tissue following the Chernobyl accident. PloS One 2012;7: e39103.
Abend M, Pfeiffer RM, Ruf C, et al. Iodine-131 dose-dependent gene expression: Alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers. Br J Cancer 2013;109:2286-2294.