Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology, De Boelelaan 1117, Amsterdam, The Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Surgery, De Boelelaan 1117, Amsterdam, The Netherlands.
Lung Cancer. 2022 Aug;170:156-164. doi: 10.1016/j.lungcan.2022.06.013. Epub 2022 Jun 22.
Lung cancer has the highest cancer-related mortality worldwide and earlier detection could improve outcomes. Urine circulating tumor DNA (ctDNA) represents a true non-invasive means for ambulant sample collection. In this prospective study, the potential of urine for perioperative detection of non-metastatic non-small cell lung cancer (NSCLC) using ctDNA methylation analysis is evaluated.
Preoperative urine samples of 46 surgical NSCLC patients and 50 sex and age-matched controls were analyzed for DNA methylation of NSCLC-associated methylation markers CDO1, SOX17, and TAC1, using quantitative methylation-specific PCR (qMSP). The accuracy for NSCLC detection was determined by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Fourteen additional urine samples were collected postoperatively to evaluate whether DNA methylation levels alter after surgery with curative intent.
Methylation levels of CDO1 and SOX17 were significantly elevated in patients compared to controls (P =.016 and P <.001, respectively). This marker combination yielded an area under the receiver operating curve (AUC) value of 0.71 upon leave-one-out cross-validation for non-metastatic NSCLC detection in urine. Stage I patients tended to have higher methylation levels of SOX17 as compared to stage III patients. Similar methylation levels were found across the different histological subtypes of NSCLC. In some patients with preoperative elevated methylation levels, reduced methylation levels were found in post-operative urine samples.
Urine CDO1 and SOX17 showed increased methylation levels in NSCLC patients as compared to sex- and age-matched controls. This demonstrates that urine ctDNA methylation analysis may provide an interesting non-invasive means to detect non-metastatic NSCLC. Further studies are needed to validate the clinical usefulness of this approach and to assess the potential of post-operative monitoring.
肺癌是全球癌症相关死亡率最高的疾病，早期发现可以改善预后。尿液循环肿瘤 DNA（ctDNA）代表了一种真正的非侵入性的门诊样本采集方法。在这项前瞻性研究中，评估了使用 ctDNA 甲基化分析检测非转移性非小细胞肺癌（NSCLC）的尿液潜力。
对 46 例手术 NSCLC 患者和 50 例性别和年龄匹配的对照者的术前尿液样本进行了与 NSCLC 相关的甲基化标记物 CDO1、SOX17 和 TAC1 的 DNA 甲基化分析，使用定量甲基化特异性 PCR（qMSP）。通过单变量和多变量逻辑回归分析，以及留一法交叉验证来确定 NSCLC 检测的准确性。术后收集了另外 14 例尿液样本，以评估根治术后 DNA 甲基化水平是否发生变化。
与对照组相比，患者的 CDO1 和 SOX17 甲基化水平显著升高（P=.016 和 P<.001）。该标志物组合在留一法交叉验证中对尿液中非转移性 NSCLC 的检测产生了 0.71 的接收者操作特征曲线（AUC）值。与 III 期患者相比，I 期患者的 SOX17 甲基化水平往往更高。不同组织学亚型的 NSCLC 具有相似的甲基化水平。在一些术前甲基化水平升高的患者中，术后尿液样本中的甲基化水平降低。
与性别和年龄匹配的对照组相比，NSCLC 患者的尿液 CDO1 和 SOX17 显示出更高的甲基化水平。这表明尿液 ctDNA 甲基化分析可能为检测非转移性 NSCLC 提供一种有趣的非侵入性方法。需要进一步的研究来验证该方法的临床实用性，并评估术后监测的潜力。
