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. 2025 Aug 22;11(34):eadw7680.
doi: 10.1126/sciadv.adw7680. Epub 2025 Aug 22.

Distinctive molecular features of radiation-induced thyroid cancers

Danielle M Karyadi  1 , Tetiana I Bogdanova  2 , Cato M Milder  3 , Stephen W Hartley  1 , Olivia W Lee  1 , Michael Dean  4 , Vladimir Drozdovitch  3 , Elizabeth K Cahoon  3 , Sergii Masiuk  5 , Mykola Chepurny  5 , Liudmyla Yu Zurnadzhy  2 , Vibha Vij  3 , Cari M Kitahara  3 , Gerry A Thomas  6 , Gayle E Woloschak  7 , Dale A Ramsden  8 , Mykola D Tronko  9 , Stephen J Chanock  1 , Lindsay M Morton  3
Affiliations

Distinctive molecular features of radiation-induced thyroid cancers

Danielle M Karyadi et al. Sci Adv. .

Abstract

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: BRAFV600E (n = 132), RAS mutation (n = 31), fusions generated from two breakpoints and <20 base pairs (bp) breakpoint gain/loss (Fusion2B<20bp; n = 63), or ≥3 breakpoints and ≥1000 bp breakpoint loss (n = 20). The frequency of Fusion2B<20bp-PTC increased with increasing thyroid radiation dose, whereas all others declined. Clonal small deletion counts increased with increasing radiation dose for Fusion2B<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 Fusion2B<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 Fusion2B<20bp-PTC as a group but not other drivers.

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Figures

Fig. 1.
Fig. 1.. Schematics of mutation accumulation in normal and tumor cells.
Accumulation of radiation-induced mutations under scenarios where radiation exposure occurred before tumor initiation (A), caused the tumor (B), or occurred after tumor initiation (C). Accumulation of clock mutations (D).
Fig. 2.
Fig. 2.. Distribution of thyroid radiation dose by the pattern of DNA damage that generated the PTC driver.
Continuous dose distribution truncated at 1000 mGy for primary driver categories (A) and categorical dose distribution for all driver categories, showing percentages ≥5% (B).
Fig. 3.
Fig. 3.. Relationship between radiation dose to the thyroid and DNA DSBs as measured by the clonal deletion:SNV ratio, by pattern of DNA damage that generated the PTC driver.
Analyses excluded unexposed individuals (i.e., born >9 months after the accident). βs per 100 mGy [95% confidence interval (CI)] were estimated from linear regression models, with adjustment for sex and age at PTC diagnosis. Radiation dose outliers were truncated at 1000 mGy for PTC with fusion drivers with two breaks, <20 bp gain/loss at both breakpoints and 300 mGy for PTC with mutation drivers; deletion:SNV ratio outliers were truncated at 0.3. Note that P = 0.039 if dose was also truncated at 300 mGy for PTC with fusion drivers with two breaks, <20 bp gain/loss at both breakpoints. Red font and line indicate regression model with statistically significant parameter estimate (P < 0.05).
Fig. 4.
Fig. 4.. Relationship between age at the time of the Chornobyl accident and clonal clock mutations, by pattern of DNA damage that generated the PTC driver.
Analyses excluded unexposed individuals (i.e., born >9 months after the accident). βs per year of age (95% CI) were estimated from linear regression models adjusted for sex and age at PTC. P values were calculated using likelihood ratio tests. Red font and line indicate regression model with statistically significant parameter estimate (P < 0.05).
Fig. 5.
Fig. 5.. Patient characteristics among exposed individuals, by pattern of DNA damage that generated the PTC driver.
Sex (A), age at exposure (B), age at PTC (C), and calendar year of PTC diagnosis (D).
See this image and copyright information in PMC

References

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