The prognostic value of a Methylome-based Malignancy Density Scoring System to predict recurrence risk in early-stage Lung Adenocarcinoma

Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery. However, 25% to 40% of patients with stage IA disease experience recurrence. Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk. However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity. Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS). Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy. Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling. A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient. A MD score was then obtained by Wald statistics. The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated. Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47, P=0.01). The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748) nor inflammatory status (p=0.548). Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69, P=0.039). In addition, multivariate analysis revealed EGFR 19 del (HR=5.39, P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion: The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.