Distinctive molecular features of radiation-induced thyroid cancers

Papillary thyroid carcinoma (PTC) incidence increased after childhood exposure to radioactive fallout from the Chornobyl accident. We investigated PTC genomic profiles to distinguish radiation-induced versus sporadic oncogenic drivers by modeling dose and molecular characteristics by driver category: BRAF V600E ( n = 132), RAS mutation ( n = 31), fusions generated from two breakpoints and <20 base pairs (bp) breakpoint gain/loss (Fusion 2B<20bp ; n = 63), or ≥3 breakpoints and ≥1000 bp breakpoint loss ( n = 20). The frequency of Fusion 2B<20bp -PTC increased with increasing thyroid radiation dose, whereas all others declined. Clonal small deletion counts increased with increasing radiation dose for Fusion 2B<20bp -PTC ( P = 5.1 × 10 −4 ) but not other drivers ( P > 0.08). Clonal clock mutational signatures, marking the age of tumor initiation, were associated with age at the accident for Fusion 2B<20bp -PTC ( P = 8.2 × 10 −4 ) but not other drivers ( P > 0.21). Together, these results support a causal role for ionizing radiation in Fusion 2B<20bp -PTC as a group but not other drivers.