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.