Childhood Exposure to Excess Ionizing Radiation Is Associated with Dose-Dependent Fusions as Molecular Drivers of Papillary Thyroid Cancer

Background: Exposure to excess ionizing radiation has been identified as a risk factor for the development of thyroid cancer (1). However, there are no well-established biomarkers indicating exposure to radiation as the etiology of thyroid tumors that can be applied in clinical care or in legal claims. Morton et al. analyzed a large cohort of individuals who were exposed to a power plant accident in Chernobyl in 1986 in their childhood and who subsequently developed papillary thyroid cancer (PTC) (2). The goal of the study was to enhance our understanding of radiation-induced carcinogenesis based on assessment of the molecular drivers, transcriptomics, and epigenetic profile of PTC associated with excessive environmental radiation exposure. Methods: The authors performed whole-genome sequencing, single-nucleotide polymorphism (SNP) microarray genotyping, mRNA and microRNA sequencing, methylation profiling, transcriptome analysis, and telomere-length quantification in 440 pathologically confirmed fresh-frozen PTC tissue samples for which matched normal tissue from either nontumor thyroid and/or blood was available. In the study group, 359 subjects were exposed to excess ionizing radiation in childhood or in utero; 81 individuals who were born more than 9 months after the Chernobyl accident served as a reference group. The data were analyzed adjusting for covariates that potentially affect PTC incidence, including sex, age at diagnosis, age at radiation exposure, and latency (defined as the time from exposure to PTC diagnosis). Results: 3 accounted for the majority of the remaining drivers (41% of the tumors). Moreover, there was a significant association between fusion drivers and radiation dose, after adjustment for age at diagnosis and sex. Same significant association with radiation was observed for small deletions and balanced structural variants resulting from the nonhomologous end-joining repair of double-stranded DNA damage. In contrast, transcriptome, methylome, or telomere length were not significantly associated with the radiation dose, and all tumors were microsatellite-stable. No novel molecular signature unique for radiation-associated PTC has been identified. Conclusions: The study reveals potential mechanisms behind radiation-associated PTC, consisting of DNA double-stranded breaks leading to nonhomologous end-joining repair mechanisms, that result in pathogenic gene fusions responsible for clonal growth. There is no unique signature of radiation-associated PTC that could serve as a biomarker of radiation-induced malignancy.