Distinguishing Features of Radiation-Induced from Sporadic Thyroid Cancers after the Chornobyl Nuclear Power Plant Accident

Recent data indicate that radiation-induced papillary thyroid carcinomas (PTC) after the 1986 Chornobyl accident can be distinguished from sporadic PTC by examining patterns of DNA damage related to the generation of oncogenic drivers. PTC with fusion/structural variant (SV) drivers generated from two breakpoints with <20 basepairs (bp) breakpoint loss/gain (fusion2B<20bp) were consistent with radiation causation based on a series of analyses, including higher frequency with increasing radiation dose and an even distribution by sex. In contrast, fusion≥3B≥1000bp-, RAS-, and BRAFV600E-driven PTC exhibited no dose association and female predominance, as observed in sporadic PTC. We conducted DNA and RNA sequencing and reconstructed thyroid radiation dose for 229 PTCs to replicate and extend previous reports. Combined analyses with 331 published PTCs enabled investigation of dose and sex distributions for additional, less common fusion/SV driver categories. Among newly characterized PTCs, only fusion2B<20bp had statistically significantly lower female predominance and higher dose compared with BRAFV600E (67.1% vs. 82.4% female, P=0.034; median dose=186 vs. 52 mGy, P=6.410-5; 0% vs. 11.0% in unexposed), replicating the previous report (pooled Psex=7.910-4; pooled Pdose=3.010-10). Analyses of additional fusion/SV driver categories revealed similarly elevated doses for fusion≥3B<20bp (N=4, median=203 mGy, P=9.210-3). Doses were also significantly higher but to a lesser extent for fusion2B<1000bp (N=34, median=131 mGy, P=6.210-4) and fusion≥3B<1000bp (N=13, median=127 mGy, P=5.010-5). Our results suggest that the amount of loss/gain at the fusion/SV driver breakpoint appears to be a more informative feature than the number of DNA DSBs for distinguishing radiation-induced from sporadic tumor groups in this dose range.