Objectives: Radon, a natural radiation, is the leading environmental cause of lung cancer in never-smokers. However, the radon exposure impact on the mutational landscape and tumor mutation burden (TMB) of lung cancer in never-smokers has not been explored. The aim of this study was to investigate the mutational landscape of lung adenocarcinoma in never-smokers who were exposed to various degrees of residential radon. Materials and methods: To investigate the effect of indoor radon exposure, we estimated the cumulative exposure to indoor radon in each house of patients with lung cancer with a never-smoking history. Patients with at least 2 year-duration of residence before the diagnosis of lung adenocarcinoma were included. Patients were subgrouped based on the median radon exposure level (48 Bq/m 3 ): radon-high vs. radon-low and targeted sequencing of tumor and matched blood were performed in all patients. Results: Among 41 patients with lung adenocarcinoma, the TMB was significantly higher in the radon-high group than it was in the radon-low group (mean 4.94 vs. 2.6 mutations/Mb, P = 0.01). The recurrence rates between radon-high and radon-low group did not differ significantly. Mutational signatures of radon-high tumors showed features associated with inactivity of the base excision repair and DNA replication machineries. The analysis of tumor evolutionary trajectories also suggested a series of mutagenesis induced by radon exposure. In addition, radon-high tumors revealed a significant protein-protein interaction of genes involved in DNA damage and repair (P < 0.001). Conclusions: Indoor radon exposure increased the TMB in never-smoker patients with lung adenocarcinoma and their mutational signature was associated with defective DNA mismatch repair.
Bibliographical noteFunding Information:
This study was supported by the Korean Ministry of Environment as part of the “Environmental Health Action Program” (grant number 2015001350002 ) and supported by a grant from the National research foundation (NRF), Republic of Korea (NRF- 2016R1C1B1013299 , NRF-2017M3A9E9072669 , NRF-2017R1D1A1B03029874 ).
This study was supported by the Korean Ministry of Environment as part of the “Environmental Health Action Program” (grant number 2015001350002) and supported by a grant from the National research foundation (NRF), Republic of Korea (NRF-2016R1C1B1013299, NRF-2017M3A9E9072669, NRF-2017R1D1A1B03029874). The biospecimens and data used for this study were provided by the Biobank of Ajou University Hospital, a member of Korea Biobank Network.
All Science Journal Classification (ASJC) codes
- Pulmonary and Respiratory Medicine
- Cancer Research