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)./nMethods: 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./nResults: 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./nConclusion: 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.

中文翻译：

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基于甲基化组的恶性肿瘤密度评分系统对预测早期肺癌的复发风险的预后价值。

当前的NCCN指南不建议对R0手术的IA期肺腺癌患者使用辅助化疗。但是，有25％至40％的IA期患者会复发。根据复发风险对患者进行分层，可以为风险较高的患者定制辅助治疗和监视影像。然而，通常通过比较高风险和低风险病例来鉴定预后标志物，由于广泛的患者间异质性可能引入偏倚。在这里，我们开发了一个评分系统量化场癌变的程度在邻近的正常组织，并透露与无病生存（DFS）./ñ其关联方法：我们招募了一组44例未接受辅助治疗的IA期肺腺癌切除患者。从每个患者中获得肿瘤和邻近的正常组织，并进行基于捕获的靶向基因组和表观基因组分析。通过比较每位患者的肿瘤和相应的相邻正常组织，基于39位患者开发了一种基于甲基化组的评分系统，即恶性密度比（MD比）。然后通过Wald统计数据获得MD评分。的MD之比，MD得分，并与临床结果的基因组特征的相关性是investigated./n结果：MD风险高的患者与MD风险低的患者相比，术后DFS明显缩短（HR = 4.47，P = 0.01）。MD比率与T期（P = 1），肿瘤细胞分数（P = 0.748）或炎症状态（p = 0.548）无关。MD评分高风险的患者也表现出较差的DFS（HR = 4.69，P = 0.039）。此外，多变量分析显示EGFR 19 del（HR = 5.39，P = 0.012）和MD评分（HR = 7.90，P = 0.01）是独立的预后指标。 通过比较单个患者的肿瘤与相应的相邻正常组织之间的特征而开发的基于甲基化的新型评分系统，极大地降低了患者间异质性的偏倚，并揭示了在切除的肺腺癌患者中具有强大的预后价值。