Abstract 6293: Distinguishing radiation-induced from sporadic thyroid cancers after the Chornobyl nuclear power plant accident.

Abstract Radioactive fallout from the 1986 Chornobyl accident increased papillary thyroid carcinoma (PTC) risk after childhood exposure. Radiation-induced versus sporadic tumors cannot be distinguished by clinical characteristics, histologic features, or known COSMIC signatures. A recent analysis examined the pattern of DNA damage that generated PTC oncogenic drivers from Chornobyl-exposed and unexposed individuals because such patterns reflect DNA repair mechanisms, e.g., healthy cells engage efficient DNA double-strand break (DSB) repair without substantial DNA loss. PTC with fusion/structural variant (SV) drivers generated from two breakpoints and <20 basepairs (bp) breakpoint gain/loss (Fusion2B<20bp) were consistent with having been caused by radiation (higher frequency with increasing radiation dose, even distribution by sex), whereas fusion/SV-driven PTC with ≥3 breakpoints and ≥1000 bp breakpoint loss (Fusion3B≥1000bp) and BRAFV600E-driven PTC exhibited no radiation dose association and strong female predominance. To investigate radiation dose and sex distributions for additional fusion/SV driver categories and replicate the previous report, we reconstructed thyroid radiation doses and sequenced 244 histologically-confirmed PTCs (Table). Radiation doses were significantly higher for all fusion/SV-driven PTC with <1000 bp breakpoint loss (P=0.0084 to 7.1×1-10), regardless of the number of fusion/SV driver breakpoints, compared with BRAFV600E-PTC, while doses were comparably low for fusion/SV-driven PTC with ≥1000 bp breakpoint loss, albeit based on small numbers. Only the Fusion2B<20bp-PTC replication group had a lower female predominance compared with BRAFV600E-PTC (67.1% vs. 79.0%, P=0.068). These results provide evidence that the amount of gain/loss at the fusion/SV driver breakpoint is a more informative feature than the number of DNA DSBs for distinguishing radiation-induced from sporadic tumors in this dose range. Citation Format: Danielle M. Karyadi, Tetiana I. Bogdanova, Stephen W. Hartley, Vladimir Drozdovitch, Sergii Masiuk, Belynda Hicks, Kristine Jones, Amy Hutchinson, Petra Lenz, Maria Brown, Aaron M. Rozeboom, Elizabeth K. Cahoon, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Vibha Vij, Cari M. Kitahara, Michael Dean, Gayle E. Woloschak, Dale A. Ramsden, Mykola D. Tronko, Stephen J. Chanock, Lindsay M. Morton. Distinguishing radiation-induced from sporadic thyroid cancers after the Chornobyl nuclear power plant accident [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6293.