Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 131; pp. 139 - 146
• Main Authors: Lim, Sun Min, Choi, Jae Woo, Hong, Min Hee, Jung, Dongmin, Lee, Chang Young, Park, Seong Yong, Shim, Hyo Sup, Sheen, Seungsoo, Kwak, Kyeong Im, Kang, Dae Ryong, Cho, Byoung Chul, Kim, Hye Ryun
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.05.2019
• Subjects: Adenocarcinoma of Lung - genetics; Adult; Aged; Air Pollutants, Radioactive - adverse effects; Air Pollution, Indoor - adverse effects; Carcinogenesis - genetics; DNA Repair - genetics; DNA Repair - radiation effects; Female; Humans; Lung Neoplasms - genetics; Male; Middle Aged; Mutagenesis - radiation effects; Mutation; Mutation - genetics; Neoplasm Staging; Non-small-cell lung cancer; Radiation Exposure - adverse effects; Radon; Radon - adverse effects; Transcriptome; Non-small-cell lung cancer; Radon; Mutation
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2019.04.002

•Radon is the leading environmental cause of lung cancer in never-smokers.•We investigated the mutational landscape in never-smokers who were exposed to residential radon.•Indoor radon exposure increased tumor mutation burden. 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. 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/m3): radon-high vs. radon-low and targeted sequencing of tumor and matched blood were performed in all patients. 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). Indoor radon exposure increased the TMB in never-smoker patients with lung adenocarcinoma and their mutational signature was associated with defective DNA mismatch repair.