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Lung Cancer. 2019 May;131:139-146. doi: 10.1016/j.lungcan.2019.04.002. Epub 2019 Apr 3.

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

Author information

1
Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam-si, Republic of Korea.
2
Severance Biomedical Science Institute, Yonsei University of College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
5
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
6
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
7
Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.
8
Institute of Genomic Cohort, Department of Preventive Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
9
Center of Biomedical Data Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
10
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Republic of Korea.
11
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: nobelg@yuhs.ac.

Abstract

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/m3): 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.

KEYWORDS:

Mutation; Non-small-cell lung cancer; Radon

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