RED blood cell DNA profiling demonstrated potential as a non-invasive approach to early gastric cancer detection, achieving 82–89% sensitivity for Stage I disease across three multicentre validation cohorts.
Early diagnosis of gastric cancer remains challenging because endoscopy is invasive and existing blood-based biomarkers have limited sensitivity. Red blood cells (RBCs), despite lacking nuclei, can retain DNA remnants associated with pathological stress. Researchers investigated whether these remnants could provide a basis for detecting gastric cancer through genome-wide profiling of red blood cell DNA (rbcDNA).
The study included 865 individuals, comprising 434 treatment-naive patients with gastric cancer and 431 controls with benign gastric conditions. Using shallow whole-genome sequencing of rbcDNA obtained from 1–2 mL of peripheral blood, the researchers identified 1,000 reproducible read-depth features that distinguished gastric cancer from non-cancer states.
A machine learning classifier was developed using reduced-dimensionality features associated with gastric cancer. The model was trained in a discovery cohort of 435 individuals, with its decision threshold fixed at 90% specificity. Its performance was subsequently assessed in a test cohort of 109 individuals and three independent multicentre validation cohorts comprising 321 individuals.
The classifier achieved an area under the receiver operating characteristic curve of 84% during nested cross-validation in the discovery cohort and 95% in the test cohort. Across the three hospital-based validation cohorts, overall sensitivity ranged from 83–90%, while sensitivity for Stage I gastric cancer ranged from 82–89%.
These findings suggest that rbcDNA profiling could identify early disease across different clinical settings. The classifier also distinguished early-stage gastric cancer from precancerous lesions and other tumours, addressing an important diagnostic challenge in identifying malignancy among patients with other gastric conditions.
The classifier detected approximately 80% of gastric cancer cases that tested negative for tumour markers, indicating potential value as a complementary diagnostic approach. Its ability to detect Stage I disease is particularly relevant given the importance of identifying gastric cancer at an early stage.
Although the results support further investigation of rbcDNA profiling as a non-invasive detection strategy, the findings establish diagnostic potential rather than routine clinical utility. The study did not report evidence that implementing the classifier improved patient outcomes or reduced the need for endoscopy.
Further research will be important to establish how rbcDNA profiling could be integrated into existing diagnostic pathways. Its performance across independent multicentre cohorts provides a basis for continued evaluation as a potential tool for earlier gastric cancer detection.
Reference
Yao X et al. Early detection of gastric cancer using DNA features in red blood cells, with multicenter validation. Med. 2026;DOI:10.1016/j.medj.2026.101325.
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