Chen, Kezhong;
Kang, Guannan;
Zhang, Zhihong;
Lizaso, Analyn;
Beck, Stephan;
Lyskjær, Iben;
Chervova, Olga;
... Wang, Jun; + view all
(2023)
Individualized dynamic methylation-based analysis of cell-free DNA in postoperative monitoring of lung cancer.
BMC Medicine
, 21
, Article 255. 10.1186/s12916-023-02954-z.
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Abstract
Background The 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.// Methods: Matched 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).// Results: Tumor-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.// Conclusions: The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance.
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