Beyond tissue biopsy: ctDNA methylation analysis for prediction of colorectal cancer prognosis.

Accurate prognostic stratification remains a major challenge in colorectal cancer (CRC), as substantial heterogeneity in clinical outcomes persists even within the same pathological stage. While mutation-based circulating tumor DNA (ctDNA) analysis has transformed postoperative risk assessment by enabling detection of molecular residual disease (MRD), it primarily reflects the presence of tumor-derived genetic alterations and may not fully capture the biological processes underlying tumor progression. DNA methylation represents a complementary molecular layer that reflects coordinated regulatory states associated with tumor behavior, including transcriptional programs and cellular plasticity. Recent studies suggest that ctDNA methylation profiling may provide additional prognostic information beyond conventional clinicopathological factors and mutation-based assays, particularly in early-stage and postoperative settings. However, important challenges remain, including assay heterogeneity, lack of standardized metrics, and the need for robust external validation. In this Perspective, we examine the limitations of current prognostic frameworks and discuss the potential role of ctDNA methylation analysis as part of an integrated, multidimensional model for risk stratification in CRC. We propose that incorporating epigenetic information may refine prognostic assessment, while emphasizing the need for rigorous validation prior to clinical implementation.