Post-Chornobyl thyroid papillary carcinomas display distinct past 131I exposure and radiation-associated carcinogenesis molecular signatures at low and high thyroid doses

Most previous studies aimed to establish etiological signatures of thyroid tumors compared sporadic papillary thyroid carcinomas (sPTC) and PTC that develop in individuals exposed to ionizing radiation during childhood. However, such approaches may lead to a biased signature combining exposure markers independent of the carcinogenic process and markers of radiation-induced carcinogenesis. We analyzed the miRNome (Affymetrix) and transcriptome (RNA sequencing) of a series of normal thyroid tissues and PTC from Ukrainian individuals contaminated with iodine-131 released by the Chornobyl Nuclear Power Plant in 1986 at high (> 0.5 Gy; N = 9) or low (< 50 mGy; N = 12) thyroid radiation doses, and from unexposed Ukrainian individuals (N = 28). First, the six sample groups were analyzed jointly using partial least squares discriminant analysis (sPLS-DA) to assess whether normal tissues and PTC shared common multi-omic signatures associated with exposure history, independent of carcinogenesis. Next, we applied a multiblock sPLS-DA (DIABLO) to isolate markers associated with exposure in the three normal tissue groups. Then, using the remaining miR and genes from the datasets not associated with exposure, we searched for a multi-omics signature associated with a difference in the carcinogenic process. sPLS-DA analysis of the six sample groups showed that normal tissues and PTC from exposed individuals shared a common multi-omics signature (58 miR/snoRNA, 50 genes) compared to unexposed samples. Our DIABLO analysis identified 44 miR/snoRNA and 45 genes exposure signatures distinguishing exposed from unexposed normal tissues. These signatures, when applied to PTC groups, supported that PTC developed after radiation exposure exibited exposure markers independent of any carcinogenic process. In addition to this exposure signature, we identified 39 miR/snoRNA and 64 genes signatures that identified the PTC developed after radiation exposure which deviated significantly from the sPTC profile. Normal tissues and PTC from exposed individuals exhibit a common molecular long-term memory of exposure history. Furthermore, PTC developed after radiation exposure display dose-dependent molecular specificities compared to sPTC. As PTC associated with low doses are mainly subclinical sPTC revealed by screening in the post-Chornobyl population, the proposed multi-omic signature could be attributable to sPTC developed in an exposed thyroid gland.