Abstract
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.