A multicenter prospective clinical trial reveals cell-free DNA methylation markers for early esophageal cancer
Ruixiang Zhang, Yongzhan Nie, Xiaobing Chen, Tao Jiang, Jinhai Wang, Yuhui Peng, Guangpeng Zhou, Yong Li, Lina Zhao, Beibei Chen, Yunfeng Ni, Yan Cheng, Yiwei Xu, Zhenyu Zhu, Xianchun Gao, Zhen Wu, Tianbao Li, Jie Zhao, Cantong Liu, Gang Zhao, Jiakuan Chen, Jing Zhao, Gang Ji, Xiaoliang Han, Jie He, Yin Li
Ruixiang Zhang, Yongzhan Nie, Xiaobing Chen, Tao Jiang, Jinhai Wang, Yuhui Peng, Guangpeng Zhou, Yong Li, Lina Zhao, Beibei Chen, Yunfeng Ni, Yan Cheng, Yiwei Xu, Zhenyu Zhu, Xianchun Gao, Zhen Wu, Tianbao Li, Jie Zhao, Cantong Liu, Gang Zhao, Jiakuan Chen, Jing Zhao, Gang Ji, Xiaoliang Han, Jie He, Yin Li
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Clinical Research and Public Health Oncology

A multicenter prospective clinical trial reveals cell-free DNA methylation markers for early esophageal cancer

Abstract

BACKGROUND Current methods for detecting esophageal cancer (EC) are generally invasive or exhibit limited sensitivity and specificity, especially for the identification of early-stage tumors.METHODS We identified potential methylated DNA markers (MDMs) from multiple genomic regions in a discovery cohort, and a diagnostic model was developed and verified in a model-verification cohort of 297 participants. The accuracy of the MDM panel was validated in a multicenter, prospective cohort (n = 1,429). The clinical performance of identified MDMs were compared with current tumor-associated protein markers.RESULTS From 31 significant differentially methylated EC-associated regions identified in the marker discovery, we trained and validated a 3-MDM diagnostic model that could discriminate among patients with EC and volunteers without EC in a multicenter clinical prospective cohort with a sensitivity of 85.5% and a specificity of 95.3%. This panel showed higher sensitivity in diagnosing early-stage tumors, with sensitivities of 56% for stage 0 and 77% for stage I, compared with the performance of current biochemical markers. In population with high risk for EC, the sensitivity and specificity were 85.68% and 93.61%, respectively.CONCLUSION The assessment of tumor-associated methylation status in blood samples can facilitate noninvasive and reliable diagnosis of early-stage EC, which warrants further development to expand screening and reduce mortality rates.TRIAL REGISTRATION ChiCTR2400083525.FUNDING Science and technology funds of Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park. Project number: Z201100005420007.

Authors

Ruixiang Zhang, Yongzhan Nie, Xiaobing Chen, Tao Jiang, Jinhai Wang, Yuhui Peng, Guangpeng Zhou, Yong Li, Lina Zhao, Beibei Chen, Yunfeng Ni, Yan Cheng, Yiwei Xu, Zhenyu Zhu, Xianchun Gao, Zhen Wu, Tianbao Li, Jie Zhao, Cantong Liu, Gang Zhao, Jiakuan Chen, Jing Zhao, Gang Ji, Xiaoliang Han, Jie He, Yin Li

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Figure 4

Multiplex detection of Septin9, Epo, and MT-1A methylation status by qMSP in the clinical validation cohorts.

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Multiplex detection of Septin9, Epo, and MT-1A methylation status by qMS...
(A) Diagnostic efficacy of the MDMs and the combined panel in the clinical validation cohort. The ROC curves indicated the performance for distinguishing esophageal cancer (n = 641, including 609 patients with esophageal cancer and 32 patients with high-grade intraepithelial neoplasia) from nonesophageal cancer (n = 788, including 198 participants with other cancers, 292 healthy participants, and 298 participants with benign esophageal diseases). (B) Confusion matrix comparing true-observed classifications (reference detection methods) with 3-MDM panel-predicted diagnoses in the clinical validation cohort. The esophageal cancer (n = 641) group, according to true-observed classifications, included 609 patients with esophageal cancer and 32 patients with high-grade intraepithelial neoplasia. The control cases (n = 590), according to true-observed classifications, included 298 patients with benign esophageal diseases and 292 healthy individuals. (C) Specificities of the 3-MDM panel in each cancer type of 198 participants with other cancers, in 292 healthy participants, and in 298 participants with benign esophageal diseases. Different sample types are listed along the vertical axis, and predictive results are shown in the heatmap, while the corresponding specificity for each sample type is shown on the right vertical axis.