Radiation-related genomic profile of papillary thyroid cancer after the Chernobyl accident

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131 I-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (359 with estimated childhood 131 I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of non-homologous end-joining repair. Radiation-related genomic alterations were more pronounced for those younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure. Post-Chernobyl papillary thyroid cancers demonstrate radiation dose-dependent increases in clonal DNA double-strand breaks.