Cell‐free epigenomes enhanced fragmentomics‐based model for early detection of lung cancer

作者：Yadong Wang, Qiang Guo, Zhicheng Huang, Liyang Song, Fei Zhao, Tiantian Gu, Zhe Feng, Haibo Wang, Bowen Li, Daoyun Wang, Bin Zhou, Chao Guo, Yuan Xu, Yang Song, Zhibo Zheng, Zhongxing Bing, Haochen Li, Haochen Li, Xiaoqing Yu, Ka Luk Fung, Haoxiang Xu, Jianhong Shi, Chen Meng, Shuai Hong, Haoxuan Jin, Shiyuan Tong, Sibo Zhu, Chen Zhu, Jinlei Song, Jing Liu, Shanqing Li, Hefei Li, Hefei Li, Xueguang Sun, Naixin Liang · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70225 · 被引用次数：15 · 研究领域：Cancer Genomics and Diagnostics、Epigenetics and DNA Methylation、Lung Cancer Treatments and Mutations

BACKGROUND: Lung cancer is a leading cause of cancer mortality, highlighting the need for innovative non-invasive early detection methods. Although cell-free DNA (cfDNA) analysis shows promise, its sensitivity in early-stage lung cancer patients remains a challenge. This study aimed to integrate insights from epigenetic modifications and fragmentomic features of cfDNA using machine learning to develop a more accurate lung cancer detection model. METHODS: To address this issue, a multi-centre prospective cohort study was conducted, with participants harbouring suspicious malignant lung nodules and healthy volunteers recruited from two clinical centres. Plasma cfDNA was analysed for its epigenetic and fragmentomic profiles using chromatin immunoprecipitation sequencing, reduced representation bisulphite sequencing and low-pass whole-genome sequencing. Machine learning algorithms were then employed to integrate the multi-omics data, aiding in the development of a precise lung cancer detection model. RESULTS: Cancer-related changes in cfDNA fragmentomics were significantly enriched in specific genes marked by cell-free epigenomes. A total of 609 genes were identified, and the corresponding cfDNA fragmentomic features were utilised to construct the ensemble model. This model achieved a sensitivity of 90.4% and a specificity of 83.1%, with an AUC of 0.94 in the independent validation set. Notably, the model demonstrated exceptional sensitivity for stage I lung cancer cases, achievi...