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 5 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 10 DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure.1The accidental explosion in reactor 4 at the Chernobyl nuclear power plant in April 1986 resulted in the exposure of millions of inhabitants of the surrounding areas of Ukraine, Belarus, and the Russian Federation to radioactive contaminants (1). Epidemiologic and clinical research in the ensuing decades has demonstrated increased risk of papillary thyroid carcinoma (PTC) with increasing thyroid gland exposure to radioactive iodine ( 131 I) from fallout, which was deposited on pastures with grazing cows and ingested through milk, particularly during early childhood (2). Together with data from populations exposed to other types of radiation, compelling evidence indicates that PTC risk increases following childhood exposure to ionizing radiation, a recognized carcinogen (2-5).Currently, there are no established molecular biomarkers for cancers induced by radiation, nor have there been large-scale analyses of the genomic landscape of human cancers occurring after a well-quantified radiation exposure. Classical cytogenetic studies have demonstrated radiation dose-associated increases in large chromosomal aberrations (such as inversions and translocations) that reflect DNA double-strand breaks and are the current standard for biodosimetry; however, these assays are typically performed in peripheral blood lymphocytes from individuals exposed to whole body irradiation and have not been directly linked to tumor characteristics (6, 7). Next-generation sequencing of 12 second primary tumors of various types that occurred within the field of previous therapeutic ionizing radiation suggested an excess of small deletions and balanced inversions (8), but radiation dose estimates were not available.RNA sequencing (RNA-seq) analyses of 65 PTCs (mean age at diagnosis=24.7 years) occurring after the Chernobyl accident identified that higher doses were associated with an increased likelihood of gene fusion drivers (9). In a genomic landscape analysis of 496 primarily unexposed PTCs (mean age at diagnosis=46.8 years; 16 patients with known prior radiation 2 exposure),...