Abstract
The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4×44 K). Associations of differential gene expression (log2(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.
Highlights
One of the most important health consequences of the 1986 Chernobyl nuclear power plant accident is a dramatic increase in thyroid cancer incidence among those who were children or adolescents at the time [1,2]
Perhaps the most compelling finding derives from a report comparing exposed and unexposed papillary thyroid cancer (PTC) cases with young age of onset from Ukraine that found a gain of chromosome band
To improve understanding of the molecular consequences of I131 exposure, we evaluated for the first time differential gene expression in thyroid tissue, defined as a difference in gene expression levels between tumor and corresponding normal thyroid tissue, in relation to individual I-131 thyroid dose estimates
Summary
One of the most important health consequences of the 1986 Chernobyl nuclear power plant accident is a dramatic increase in thyroid cancer incidence among those who were children or adolescents at the time [1,2]. Numerous epidemiological studies have established that this is primarily related to iodine-131 (I-131) exposure from the accident to the thyroid gland [3,4,5,6,7]. Earlier post-Chernobyl studies reported genetic differences between radiation-related and sporadic tumors, including specific RET/PTC gene rearrangements [10,11,12]. Subsequent analyses utilizing the CTB samples attributed the associations to the younger age of Chernobyl-exposed patients rather than to their radiation exposure [13,14]. Perhaps the most compelling finding derives from a report comparing exposed and unexposed papillary thyroid cancer (PTC) cases with young age of onset from Ukraine that found a gain of chromosome band
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