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

Sun Min Lim, Jae Woo Choi, Min Hee Hong, Dongmin Jung, Chang Young Lee, Seong Yong Park, Hyo Sup Shim, Seungsoo Sheen, Kyeong Im Kwak, Dae Ryong Kang, ByoungChul Cho, Hye Ryun Kim

Research output: Contribution to journalArticle

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/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.

Original languageEnglish
Pages (from-to)139-146
Number of pages8
JournalLung Cancer
Volume131
DOIs
Publication statusPublished - 2019 May 1

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Radon
Tumor Burden
Mutation
Lung Neoplasms
Adenocarcinoma of lung
DNA Repair
Neoplasms
Background Radiation
DNA Mismatch Repair
DNA Replication

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Lim, S. M., Choi, J. W., Hong, M. H., Jung, D., Lee, C. Y., Park, S. Y., ... Kim, H. R. (2019). Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma. Lung Cancer, 131, 139-146. https://doi.org/10.1016/j.lungcan.2019.04.002
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, ByoungChul ; Kim, Hye Ryun. / Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma. In: Lung Cancer. 2019 ; Vol. 131. pp. 139-146.
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title = "Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma",
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/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.",
author = "Lim, {Sun Min} and Choi, {Jae Woo} and Hong, {Min Hee} and Dongmin Jung and Lee, {Chang Young} and Park, {Seong Yong} and Shim, {Hyo Sup} and Seungsoo Sheen and Kwak, {Kyeong Im} and Kang, {Dae Ryong} and ByoungChul Cho and Kim, {Hye Ryun}",
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Lim, SM, Choi, JW, Hong, MH, Jung, D, Lee, CY, Park, SY, Shim, HS, Sheen, S, Kwak, KI, Kang, DR, Cho, B & Kim, HR 2019, 'Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma', Lung Cancer, vol. 131, pp. 139-146. https://doi.org/10.1016/j.lungcan.2019.04.002

Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma. / 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, ByoungChul; Kim, Hye Ryun.

In: Lung Cancer, Vol. 131, 01.05.2019, p. 139-146.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma

AU - Lim, Sun Min

AU - Choi, Jae Woo

AU - Hong, Min Hee

AU - Jung, Dongmin

AU - Lee, Chang Young

AU - Park, Seong Yong

AU - Shim, Hyo Sup

AU - Sheen, Seungsoo

AU - Kwak, Kyeong Im

AU - Kang, Dae Ryong

AU - Cho, ByoungChul

AU - Kim, Hye Ryun

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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