GUIDE: a prospective cohort study for blood-based early detection of gastrointestinal cancers using targeted DNA methylation and fragmentomics sequencing

作者：Ao Huang, De‐Zhen Guo, Zhixi Su, Yunshi Zhong, Liang Liu, Zhiguo Xiong, Dong-Li He, Bin Yan, Quan‐Lin Li, Zhen Feng, Wenquan Wang, Pinxiang Lu, Meng‐Jiang He, Zhipeng Qi, Qi Guo, Jianwen Cheng, Shiyu Zhang, Wei Guo, Qing Li, Guo-Yong Lin, Hui‐Chuan Sun, Shuang–Jian Qiu, Qiye He, Jia Fan, Ajay Goel, Rui Liu, Gang Jin, Xin‐Rong Yang, Jian Zhou · 发表于：Molecular Cancer · 年份：2025 · DOI：10.1186/s12943-025-02367-x · 被引用次数：12 · 研究领域：Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics、Esophageal Cancer Research and Treatment

BACKGROUND: Gastrointestinal (GI) cancers are among the most prevalent and lethal malignancies worldwide. Early, non-invasive detection is essential for timely intervention and improved survival. To address this clinical need, we developed GutSeer, a blood-based assay combining DNA methylation and fragmentomics for multi-GI cancer detection. METHODS: Genome-wide methylome profiling identified 1,656 markers specific to five major GI cancers and their tissue origins. Based on these findings, we designed GutSeer, a targeted bisulfite sequencing panel, which was trained and validated using plasma samples from 1,057 cancer patients and 1,415 non-cancer controls. The locked model was blindly tested in an independent cohort of 846 participants, encompassing both inpatient and outpatient settings across five hospitals. RESULTS: In the validation cohort, GutSeer achieved an area under the curve (AUC) of 0.950 [95% Confidence Interval (CI): 0.937-0.962] for cancer detection, with 82.8% sensitivity (95% CI: 79.5-86.0) and 95.8% specificity (95% CI: 94.3-97.2). It detected 92.2% of colorectal, 75.5% of esophageal, 65.3% of gastric, 92.9% of liver, and 88.6% of pancreatic cancers. The independent test cohort included 198 early-stage cancers (stage I/II, 66.4%) and 63 advanced precancerous lesions. GutSeer maintained robust performance, with 81.5% sensitivity (95% CI: 77.1-85.9) for GI cancers and 94.4% specificity (95% CI: 92.4-96.5). It also demonstrated the ability to detect advanced pr...