Background: Non-Small Cell Lung Cancer (NSCLC) remains a challenging disease to manage with effectiveness. Early detection and precise monitoring are crucial for improving patient outcomes. Circulating tumor DNA (ctDNA) offers a non-invasive cancer detection and monitoring method. Emerging biomarkers, such as ctDNA methylation, have shown promise in enhancing diagnostic accuracy and prognostic assessment in NSCLC. In this review, we examined the current evidence regarding ctDNA methylation’s role in NSCLC detection through a systematic review of the existing literature and meta-analysis.Methods: We systematically searched PubMed, Medline, Embase, and Web of Science databases up to 26 June 2024 for studies on the role of ctDNA methylation analysis in NSCLC patients. We included studies from 2010 to 2024 on NSCLC patients. We excluded case reports, non-English articles, studies on cell lines or artificial samples, those without cfDNA detection, prognostic studies, and studies with non-extractable data or mixed cancer types. Funnel plots were visually examined for potential publication bias, with apvalue < 0.05 indicating bias. Meta-analysis was conducted using R packages (meta, forestplot, and mada). Combined sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR−), positive and negative predictive values, diagnostic odds ratio (DOR), and 95% confidence intervals (95% CI) were calculated. A summary receiver operating characteristic curve (SROC) and area under the curve (AUC) with related Standard Error (SE) were used to evaluate the overall diagnostic performance. Additionally,RASSF1A,APC,SOX17,SEPT9,andRARβ2were analyzed, since their methylation was assessed in two or more studies.Results: From 38 candidate papers, we finally identified 12 studies, including 472 NSCLC patients. The pooled sensitivity was 0.62 (0.47–0.77) and the specificity was 0.90 (0.85–0.94). The diagnostic odds ratio was 15.6 (95% CI 9.36–26.09) and the area under the curve was 0.249 (SE = 0.138). The positive and negative predictive values were 5.38 (95% CI 3.89–7.44) and 0.34 (95% CI 0.22–0.54), respectively. For single genes, the specificity reached 0.83~0.96, except forRARβ2, but the sensitivity was relatively low for each gene. Significant heterogeneity across the included studies, the potential publication bias for specificity (p= 0.0231), and the need to validate the clinical utility of ctDNA methylation for monitoring treatment response and predicting outcomes in NSCLC patients represent the main limitations of this study.Conclusions:These results provide evidence of the significant potential of ctDNA methylation as a valuable biomarker for improving the diagnosis of NSCLC, advocating for its integration into clinical practice to enhance patient management.
背景：非小细胞肺癌（NSCLC）的治疗仍面临挑战，早期发现与精准监测对改善患者预后至关重要。循环肿瘤DNA（ctDNA）提供了一种无创的癌症检测与监测方法。新兴生物标志物如ctDNA甲基化，在提升NSCLC诊断准确性与预后评估方面展现出潜力。本综述通过对现有文献的系统回顾与荟萃分析，探讨了ctDNA甲基化在NSCLC检测中的作用。 方法：我们系统检索了截至2024年6月26日的PubMed、Medline、Embase和Web of Science数据库中关于ctDNA甲基化分析在NSCLC患者中作用的研究。纳入2010年至2024年间针对NSCLC患者的研究，排除病例报告、非英文文献、基于细胞系或人工样本的研究、未进行cfDNA检测的研究、预后研究以及数据无法提取或涉及混合癌症类型的研究。通过漏斗图直观评估潜在发表偏倚，p值<0.05表示存在偏倚。使用R软件包（meta、forestplot和mada）进行荟萃分析，计算合并敏感性、特异性、阳性似然比（LR+）、阴性似然比（LR−）、阳性与阴性预测值、诊断比值比（DOR）及95%置信区间（95% CI）。采用综合受试者工作特征曲线（SROC）和曲线下面积（AUC）及相关标准误（SE）评估整体诊断性能。此外，对RASSF1A、APC、SOX17、SEPT9和RARβ2进行了单独分析，因其甲基化状态在两项及以上研究中被评估。 结果：从38篇候选文献中最终纳入12项研究，共涉及472例NSCLC患者。合并敏感性为0.62（0.47–0.77），特异性为0.90（0.85–0.94）。诊断比值比为15.6（95% CI 9.36–26.09），曲线下面积为0.249（SE = 0.138）。阳性预测值与阴性预测值分别为5.38（95% CI 3.89–7.44）和0.34（95% CI 0.22–0.54）。在单个基因分析中，除RARβ2外，各基因特异性达0.83~0.96，但敏感性均相对较低。本研究的主要局限性包括纳入研究间存在显著异质性、特异性存在潜在发表偏倚（p=0.0231），以及需进一步验证ctDNA甲基化在监测NSCLC患者治疗反应和预测预后方面的临床效用。 结论：这些结果证实了ctDNA甲基化作为改善NSCLC诊断的重要生物标志物具有显著潜力，支持将其整合到临床实践中以优化患者管理。
肿瘤(癌症)患者之家