Conclusions:

To our knowledge, this is the first attempt to elucidate the pathobiology of Rn induced lung cancer using gene mutation analyses. Our observations suggest that high Rn exposure induces dsDNA breaks, which constitutes an oncogenic hit in cells which are unable to efficiently repair them because of defective DNA repair pathway. • Lung cancers from high radon zones overall demonstrate a significantly higher TMB than in low radon zones, particularly in adenocarcinoma histology. • TP53, Chromatin Remodeling and KEAP1-NRF2 pathways were significantly higher in high radon zones where Receptor Tyrosine Kinase pathway was significantly lower in high radon zones. • Assuming uniform tobacco smoke exposure, higher Rn was not associated with EGFR mut.