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

• Published in: Nature communications Vol. 15; no. 1; p. 3700
• Main Authors: Liu, Jiaqi, Dai, Lijun, Wang, Qiang, Li, Chenghao, Liu, Zhichao, Gong, Tongyang, Xu, Hengyi, Jia, Ziqi, Sun, Wanyuan, Wang, Xinyu, Lu, Minyi, Shang, Tongxuan, Zhao, Ning, Cai, Jiahui, Li, Zhigang, Chen, Hongyan, Su, Jianzhong, Liu, Zhihua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/337/176/1988; 692/4028/67/1504/1477; 692/4028/67/1857; Aged; Biomarkers, Tumor - genetics; Bisulfite; Cell-Free Nucleic Acids - blood; Cell-Free Nucleic Acids - genetics; Copy number; DNA Copy Number Variations; DNA Methylation; Early Detection of Cancer - methods; Epigenome; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - diagnosis; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - diagnosis; Esophageal Squamous Cell Carcinoma - genetics; Esophagus; Female; Fragmentation; Gene sequencing; Genomes; Humanities and Social Sciences; Humans; Lesions; Male; Metastases; Methylation; Microenvironments; Middle Aged; multidisciplinary; Neoplasms; Precancerous Conditions - diagnosis; Precancerous Conditions - genetics; Precancerous Conditions - pathology; Science; Science (multidisciplinary); Sequencing; Squamous cell carcinoma; Survival; Tumor microenvironment; Tumor Microenvironment - genetics; Whole Genome Sequencing - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47886-1

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. Esophageal squamous cell carcinoma is most commonly detected at a late stage, which limits survival and treatment options. Here, the authors utilise whole genome bisulfite sequencing to create a cfDNA framework to detect cfDNA methylation, copy number variants and fragmentation.