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The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131I-exposed children. To investigate the contribution of environmental radiation to PTC characteristics and improve understanding of radiation-induced carcinogenesis, we analyzed genomic, transcriptomic, and epigenomic characteristics of 440 pathologically-confirmed fresh-frozen PTCs from Ukraine (359 with estimated childhood or in utero 131I exposure and 81 from unexposed children born after March 1987) and matched normal tissue (non-tumor thyroid tissue and/or blood). Mean age at PTC was 28.0 years (range: 10.0-45.6). Among 131I-exposed individuals, mean radiation dose was 250 mGy (range: 11.0-8,800). In multivariable models adjusted for age at PTC and sex, we observed radiation dose-dependent enrichment of fusion drivers (P=6.6 × 10−8), nearly all occurring in the MAPK pathway, as well as increases in small deletions (P=8.0 × 10−9) and simple/balanced structural variants (P=1.2 × 10−14). Further analyses demonstrated even stronger associations for those small deletions and simple/balanced structural variants that were clonal and bore hallmarks of non-homologous end-joining repair (deletions: P=4.9 × 10−31; simple/balanced structural variants: P=5.5 × 10−19). In contrast, radiation dose was not associated with subclonal small deletions (P=0.82) or subclonal simple/balanced structural variants (P=0.91). Additionally, radiation dose was not associated with TINS (locally templated insertions), which are characteristic of alt-end-joining repair (P=0.69). The effects of radiation on genomic alterations with more pronounced for those younger at exposure. Analyses generally were consistent with a linear radiation dose-response for all molecular characteristics except clonal small deletions. Analyses of transcriptomic and epigenomic features demonstrated strong associations with the PTC driver gene 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. Citation Format: Lindsay M. Morton, Danielle Karyadi, Chip Stewart, Tetiana Bogdanova, Eric Dawson, Mia Steinberg, Jieqiong Dai, Stephen Hartley, Sara Schonfeld, Joshua Sampson, Yosi Maruvka, Vidushi Kapoor, Dale Ramsden, Juan Carvajal-Garcia, Chuck Perou, Joel Parker, Marko Krznaric, Meredith Yeager, Joseph Boland, Amy Hutchinson, Belynda Hicks, Casey Dagnall, Julie Gastier-Foster, Jay Bowen, Olivia Lee, Mitchell Machiela, Elizabeth Cahoon, Alina Brenner, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Maureen Hatch, Amy Berrington de Gonzalez, Gerry Thomas, Mykola Tronko, Gad Getz, Stephen Chanock. Molecular characterization of papillary thyroid cancer in relation to ionizing radiation dose following the Chernobyl accident [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-055.