State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Nat Commun. 2024 May 2;15(1):3700. 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.
检测早期食管鳞状细胞癌 (ESCC) 和癌前病变对于提高生存率至关重要。在这里，我们对 460 例来自非转移性 ESCC 或癌前病变患者和匹配的健康对照者的 cfDNA 样本进行全基因组亚硫酸氢盐测序 (WGBS)。我们开发了一种扩展的多模态分析 (EMMA) 框架，以同时识别 cfDNA WGBS 数据中的 cfDNA 甲基化、拷贝数变异 (CNV) 和片段化标记。cfDNA 甲基化标记是最早和最敏感的，可在 70%的 ESCC 和 50%的癌前病变中检测到，与分子亚型和肿瘤微环境相关。CNV 和片段化特征具有很高的特异性，但与晚期疾病相关。EMMA 显著提高了检测率，将 AUC 从 0.90 提高到 0.99，在验证队列中，特异性 >95%时，检测到 87%的 ESCC 和 62%的癌前病变。我们的研究结果表明，cfDNA 甲基组的多模态分析具有早期检测和监测 ESCC 分子特征的潜力。
