Distinctive molecular features of radiation-induced thyroid cancers

Area of Science:

• Oncology
• Genomics
• Radiation Biology

Background:

• Papillary thyroid carcinoma (PTC) incidence rose following Chernobyl's radioactive fallout, particularly in children.
• Understanding the specific genomic drivers of radiation-induced PTC is crucial for distinguishing them from sporadic cases.

Purpose of the Study:

• To investigate papillary thyroid carcinoma (PTC) genomic profiles and molecular characteristics in relation to Chernobyl radiation dose.
• To differentiate radiation-induced oncogenic drivers from sporadic drivers based on dose and molecular features.

Main Methods:

• Genomic profiling of PTC cases (n=246) categorized by driver: BRAF^V600E, RAS mutation, Fusion^2B<20bp, or ≥3 breakpoints/≥1000 bp loss.
• Modeling of radiation dose and molecular characteristics (e.g., breakpoint counts, deletion counts, mutational signatures) against driver categories.

Main Results:

• Fusion^2B<20bp-PTC frequency significantly increased with higher thyroid radiation doses, while other drivers declined.
• Clonal small deletion counts and clonal clock mutational signatures correlated with radiation dose and age at exposure specifically for Fusion^2B<20bp-PTC.
• No significant association between radiation dose and molecular characteristics was observed for BRAF^V600E, RAS mutation, or the ≥3 breakpoints/≥1000 bp loss PTC groups.

Conclusions:

• The findings strongly support a causal role for ionizing radiation in the development of Fusion^2B<20bp-PTC.
• Specific genomic alterations in Fusion^2B<20bp-PTC serve as biomarkers for radiation exposure, distinguishing them from other PTC subtypes.