Non-Invasive Strategy for Gastric Cancer Detection: Integration of Cell-free DNA Fragmentomics and Protein Biomarkers

Gastric cancer (GC) ranks as the fifth most common cancer worldwide, however, accurate and non-invasive diagnostic modalities for GC remain limited. Cell-free DNA (cfDNA) fragmentomics has emerged as a promising tool for cancer cell detection. Here we develop a gastric cancer detection model, named GaFraD model. The GaFraD model uses four cfDNA fragmentomics features, including fragment size ratio (FSR), copy number variation (CNV), 9-bp end motif (Motif), and fragment size at transcription start sites (TF). This model achieves an area under the receiver-operating characteristic curve (AUC) of 0.970 (95% CI: 0.944 - 0.990), a sensitivity of 95.0% and a specificity of 80.9%. By combining the GaFraD model and conventional protein biomarkers CA19-9 and PG-I/PG-II, the CONFIRM model was generated. The CONFIRM model attained an AUC of 0.986 (95% CI: 0.966 - 1.000), a sensitivity of 95.0% and a specificity of 95.6% in detecting GC. Moreover, the CONFIRM model achieved remarkable performance (AUC = 0.983, sensitivity 95.6%, specificity 94.2%) in distinguishing patients with early-stage GC from controls. Our work showed the high discriminatory power in distinguishing GC patients from controls, indicating the clinical potential of using cfDNA fragmentomics combined with protein biomarkers for non-invasive GC detection. The results of the study provide a new avenue for early, accurate, and non-invasive clinical diagnosis of GC.