Colorectal cancer (CRC) is a major cause of cancer-related mortality, highlighting the need for accurate and non-invasive diagnostics. This study assessed the utility of tumor-associated circulating transcripts (TACTs) as biomarkers for CRC detection and integrated these markers into machine learning models to enhance diagnostic performance. We evaluated five models—Generalized Linear Model, Random Forest, Gradient Boosting Machine, Deep Neural Network (DNN), and AutoML—and identified the DNN model as optimal owing to its high sensitivity (85.7%) and specificity (90.9%) for CRC detection, particularly in early-stage cases. Our findings suggest that combining TACT markers with AI-based analysis provides a scalable and precise approach for CRC screening, offering significant advancements in non-invasive cancer diagnostics to improve early detection and patient outcomes.

Colorectal cancer progresses through a well-defined adenoma–carcinoma sequence (ACS), which is pivotal for early detection and intervention. While ACS-based surveillance has been instrumental, its reliance on tissue sampling limits accurate staging. Liquid biopsies, including circulating tumor DNA (ctDNA) and extracellular RNA, have emerged as non-invasive alternatives, yet they primarily detect genetic alterations or passive RNA release rather than active biological processes. Thus, there is a need for biomarkers that reflect real-time immune responses and tumor–microenvironment interactions during ACS progression. This study aimed to identify circulating RNA biomarkers associated with ACS by analyzing blood samples from 160 individuals across five groups: colorectal cancer, advanced adenoma, non-advanced adenoma, symptomatic non-disease control, and healthy control. RNA sequencing coupled with gene ontology and protein–protein interaction analyses identified stage-specific circulating transcripts. Notably, IFI27 was linked to the symptomatic non-disease control group, DEFA4 to the non-advanced adenoma group, MPO to the advanced adenoma group, and CD177 to the colorectal cancer group. These findings suggest that colorectal-cancer-related circulating RNA markers reflect host immune responses during ACS progression, supporting their potential role in early detection and non-invasive diagnoses. By addressing critical gaps in early colorectal cancer detection, this study advances the utility of circulating RNA biomarkers and liquid biopsies in colorectal cancer screening and clinical management.