• Kezhong Chen, Guannan Kang, Zhihong Zhang, Analyn Lizaso, Stephan Beck, Iben Lyskjær, Olga Chervova, Bingsi Li, Haifeng Shen, Chenyang Wang, Bing Li, Heng Zhao, Xi Li, Fan Yang, Nnennaya Kanu, and Jun Wang.
• Thoracic Oncology Institute and Department of Thoracic Surgery, Peking University People's Hospital, Beijing, 100044, China. chenkezhong@pkuph.edu.cn.
• Bmc Med. 2023 Jul 14; 21 (1): 255255.

BackgroundThe feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients.MethodsMatched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36).ResultsTumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48-6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96-8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse.ConclusionsThe dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance.Trial RegistrationThis study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 .© 2023. The Author(s).

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