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

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  • Jiaqi Liu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    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)

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.

Suggested Citation

  • 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 & Hon, 2024. "Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47886-1
    DOI: 10.1038/s41467-024-47886-1
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