Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions

Jiaqi Liu, Lijun Dai, Qiang Wang, Chenghao Li, Zhichao Liu, Tongyang Gong, Hengyi Xu, Ziqi Jia, Wanyuan Sun, Xinyu Wang, Minyi Lu, Tongxuan Shang, Ning Zhao, Jiahui Cai, Zhigang Li, Hongyan Chen (), Jianzhong Su () and Zhihua Liu ()
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Jiaqi Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Lijun Dai: Wenzhou Medical University
Qiang Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Chenghao Li: Wenzhou Medical University
Zhichao Liu: Shanghai Jiao Tong University School of Medicine
Tongyang Gong: Chinese Academy of Medical Sciences and Peking Union Medical College
Hengyi Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Ziqi Jia: Chinese Academy of Medical Sciences and Peking Union Medical College
Wanyuan Sun: Chinese Academy of Medical Sciences and Peking Union Medical College
Xinyu Wang: Wenzhou Medical University
Minyi Lu: Chinese Academy of Medical Sciences and Peking Union Medical College
Tongxuan Shang: Chinese Academy of Medical Sciences and Peking Union Medical College
Ning Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Jiahui Cai: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhigang Li: Shanghai Jiao Tong University School of Medicine
Hongyan Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Jianzhong Su: Wenzhou Medical University
Zhihua Liu: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.

Date: 2024
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DOI: 10.1038/s41467-024-47886-1

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