Abstract
Colorectal cancer (CRC) is the fourth most common cancer and the third leading cause of cancer-related mortality worldwide, with incidence rising among younger populations. The significant clinical and economic burden highlights the need for minimally invasive technologies capable of detecting pre-malignant and early-stage disease. Although liquid biopsy approaches have advanced, they have not achieved sufficient performance for clinical adoption when compared with colonoscopy, the current diagnostic gold standard. CRC is a mucosal pathology, yet current diagnostic methods have not leveraged mucosal biology. Here we demonstrate the clinical utility of rectal mucus specimens, collected using a minimally invasive device in an outpatient setting, without bowel preparation. Through a hologenomic approach integrating host and microbial genomics, we identify genetic and epigenetic aberrations and perturbations in microbial communities that drive the detection of adenomatous polyps and CRC in rectal mucus. Hologenomic integration enables superior stratification of CRC by disease site and stage compared with single-omics methods. In summary, we demonstrate the clinical utility of rectal mucus sampling combined with hologenomic analysis as a translatable prospective tool for diagnostic application.