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Lung cancer
Original research
Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China
  1. Mohammad L Rahman1,
  2. Charles E Breeze1,
  3. Xiao-Ou Shu2,
  4. Jason Y Y Wong1,
  5. Batel Blechter1,
  6. Andres Cardenas3,
  7. Xuting Wang4,
  8. Bu-Tian Ji1,
  9. Wei Hu1,
  10. Qiuyin Cai5,
  11. H Dean Hosgood6,
  12. Gong Yang7,
  13. Jianxin Shi1,
  14. Jirong Long7,
  15. Yu-Tang Gao8,
  16. Douglas A Bell4,
  17. Wei Zheng2,
  18. Nathaniel Rothman1,
  19. Qing Lan1
  1. 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
  2. 2 Vanderbilt University Medical Center, Nashville, Tennessee, USA
  3. 3 Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA
  4. 4 Immunity, Inflammation and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
  5. 5 Vanderbilt University, Nashville, Tennessee, USA
  6. 6 Albert Einstein College of Medicine, Bronx, New York, USA
  7. 7 Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
  8. 8 Shanghai Cancer Institute, Shanghai, China
  1. Correspondence to Dr Mohammad L Rahman, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA; mohammad.rahman2{at}nih.gov

Abstract

Background The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

Methods We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women’s Health Study and Shanghai Men’s Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis.

Results Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10−8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34).

Conclusions While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

  • smoking
  • lung cancer
  • non-small cell lung cancer
  • tobacco and the lung

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data generated or analysed during this study are included in this published article and its supplementary information files. For original data, please contact the corresponding author, MLR, at mohammad.rahman2@nih.gov.

https://doi.org/10.1136/thorax-2023-220352

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. All data generated or analysed during this study are included in this published article and its supplementary information files. For original data, please contact the corresponding author, MLR, at mohammad.rahman2@nih.gov.

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    Footnotes

    • X @MohammadLRahma2

    • MLR, CEB and X-OS contributed equally.

    • Presented at This research was accepted for a presentation at the 2023 Annual American Association for Cancer Research (AACR) Meeting, and an associated abstract is available in publication.

    • Contributors NR, QL, WZ and X-OS designed the study and supervised data collection. MLR, CB, JYYW and DAB prepared the analysis plan. MLR led data analysis and drafting the manuscript while CEB assisted in the process. MLR, CB, X-OS, JYYW, BB, AC, XW, B-TJ, WH, QC, HDH, GY, JS, JL, Y-TG, DAB, WZ, NR and QL contributed to the interpretation of the results and revision of the manuscript for important intellectual content and approved the final version of the manuscript. MLR and QL are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data. WZ, NR and QL cosupervised this work. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

    • Funding This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and the National Institute of Environmental Health Sciences of National Institutes of Health (research grants R01 CA70867, CA082729, UM1 CA173640).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Author note JYYW is currently at the Epidemiology and Community Health Branch, National Heart, Lung and Blood Institute. This work was conducted while formerly at the Division of Cancer Epidemiology and Genetics, National Cancer Institute.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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