通过循环肿瘤DNA甲基化对肺结节的非侵入性诊断：一项前瞻性多中心研究
Non-invasive diagnosis of pulmonary nodules by circulating tumor DNA methylation: A prospective multicenter study
影响因子:4.40000
分区:医学2区 / 肿瘤学3区 呼吸系统3区
发表日期:2024 Sep
作者:
Ying Li, Fangfang Xie, Qiang Zheng, Yujun Zhang, Wei Li, Minjie Xu, Qiye He, Yuan Li, Jiayuan Sun
摘要
随着计算机断层扫描的普及，正在检测到越来越多的肺结核（PN）。 PNS的风险分层对于检测早期肺癌的同时最小化良性结节过度诊断至关重要。这项研究旨在开发基于PNS的风险分层的基于循环的肿瘤DNA（CTDNA）甲基化的非侵入性模型。基于血液的测定法（“肺trac”）旨在包括新型的肺癌ctDNA甲基化标记物，这些肺癌CTDNA甲基化标记物是从内部降低的代表性Bisulfite bisulfite序列序列数据和已知的已知标记物中鉴定出的。基于183个CTDNA样品衍生自良性或恶性PNS的患者，并在62例患者中进行了验证，对分层模型进行了训练。在单中心和多中心队列中进一步测试了肺部TRAC。在验证集中，肺部模型在曲线（AUC）下达到了一个0.810（敏感性= 74.4％，特异性= 73.7％）的区域。使用两个测试集评估肺TRAC的性能，在单中心测试中的AUC为0.815（n = 61；灵敏度= 67.5％，特异性= 76.2％），在多中心测试中（n = 95;灵敏度= 50.7％= 50.7％且特异性= 80.8％）。通过将其与两个已建立的风险分层模型进行比较：Mayo诊所和退伍军人给药模型，进一步评估了肺部TRAC的临床实用性。它在验证和单中心测试集中的表现都胜过。该肺部TRAC模型在分层PNS方面表现出了针对恶性肿瘤风险的精确性和一致性，这表明其作为对早期外周外肺癌的非侵入性诊断辅助的实用性。
Abstract
With the popularization of computed tomography, more and more pulmonary nodules (PNs) are being detected. Risk stratification of PNs is essential for detecting early-stage lung cancer while minimizing the overdiagnosis of benign nodules. This study aimed to develop a circulating tumor DNA (ctDNA) methylation-based, non-invasive model for the risk stratification of PNs.A blood-based assay ("LUNG-TRAC") was designed to include novel lung cancer ctDNA methylation markers identified from in-house reduced representative bisulfite sequencing data and known markers from the literature. A stratification model was trained based on 183 ctDNA samples derived from patients with benign or malignant PNs and validated in 62 patients. LUNG-TRAC was further single-blindly tested in a single- and multi-center cohort.The LUNG-TRAC model achieved an area under the curve (AUC) of 0.810 (sensitivity = 74.4 % and specificity = 73.7 %) in the validation set. Two test sets were used to evaluate the performance of LUNG-TRAC, with an AUC of 0.815 in the single-center test (N = 61; sensitivity = 67.5 % and specificity = 76.2 %) and 0.761 in the multi-center test (N = 95; sensitivity = 50.7 % and specificity = 80.8 %). The clinical utility of LUNG-TRAC was further assessed by comparing it to two established risk stratification models: the Mayo Clinic and Veteran Administration models. It outperformed both in the validation and the single-center test sets.The LUNG-TRAC model demonstrated accuracy and consistency in stratifying PNs for the risk of malignancy, suggesting its utility as a non-invasive diagnostic aid for early-stage peripheral lung cancer.www.gov (NCT03989219).