Research Paper Volume 12, Issue 11 pp 10642—10662

Epigenome-wide gene–age interaction analysis reveals reversed effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients

Chao Chen1,2, *, , Yongyue Wei1,2,3, *, , Liangmin Wei1, , Jiajin Chen1, , Xin Chen1, , Xuesi Dong1,4, , Jieyu He1, , Lijuan Lin1,3, , Ying Zhu1, , Hui Huang1, , Dongfang You1,3, , Linjing Lai1, , Sipeng Shen1,2,3, , Weiwei Duan1,5, , Li Su2,3, , Andrea Shafer6, , Thomas Fleischer7, , Maria Moksnes Bjaanæs7, , Anna Karlsson8, , Maria Planck8, , Rui Wang9, , Johan Staaf8, , Åslaug Helland7,10, , Manel Esteller11,12,13,14, , Ruyang Zhang1,2,3,9, , Feng Chen1,2,15,16, , David C. Christiani3,6, #, ,

  • 1 Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
  • 2 China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
  • 3 Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
  • 4 Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing 210009, Jiangsu, China
  • 5 Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, Jiangsu, China
  • 6 Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
  • 7 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo 0424, Norway
  • 8 Division of Oncology and Pathology, Department of Clinical Sciences Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund 22381, Sweden
  • 9 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu China
  • 10 Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway
  • 11 Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, 08021, Catalonia, Spain
  • 12 Centro de Investigacion Biomedica en Red Cancer, Madrid 28029, Spain
  • 13 Institucio Catalana de Recerca i Estudis Avançats, Barcelona 08010, Catalonia, Spain
  • 14 Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona 08007, Catalonia, Spain
  • 15 State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
  • 16 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
* Equal contribution
# Senior author

Received: November 13, 2019       Accepted: April 27, 2020       Published: June 8, 2020
How to Cite

Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation–age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation–age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354PRODH, with effects significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986–0.994; P = 9.18×10–7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard (HRyoung = 2.44; 95% CI: 1.26–4.72; P = 8.34×10-3; HRelderly = 0.58; 95% CI: 0.42–0.82; P = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354PRODH methylation and elderly age (HRinteraction = 0.21; 95% CI: 0.11–0.40; P = 2.20×10−6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.


NSCLC: non-small cell lung cancer; LUSC: lung squamous cell carcinoma; LUAD: lung adenocarcinoma; TCGA: The Cancer Genome Atlas; BoCI: boundary of 95% CI; UN: United Nations; QC: quality control; HR: hazard ratio; CI: confidence interval; SD: standard deviation; PRODH: proline dehydrogenase.