The Methylation Level of Circulating Tumor DNA Predicts Prognosis for Stage I-III Colorectal Cancer

Purpose: Colorectal cancer (CRC) remains a significant health burden worldwide. Although some clinicopathological factors have been identified in stage I-III CRCs, there is a need to identify new prognostic factors. This study aimed to investigate the clinical utility of circulating tumor DNA (ctDNA) methylation analysis in predicting the prognosis of stage I-III CRCs. Methods: Methylation analyses were performed on 273 preoperative plasma samples from CRC patients who underwent surgery at Juntendo University Hospital between 2011 and 2019. The methylation levels of three tumor suppressor genes (CHFR, SOX11 and CDO1) were analyzed as relative methylation value (RMV). Results: There were no significant differences in the methylation levels of each gene among different stages of CRC. However, multivariate analysis revealed that the methylation level of SOX11 was an independent prognostic factor (Hazard ratio (HR) = 2.37 (1.20–4.67), p = 0.01). Subgroup analysis of stage III CRC also showed methylation levels of SOX11 and CDO1 were independent prognostic factors (HR = 2.66 (1.16–6.07), p = 0.02 and HR = 2.51 (1.06–5.94), p = 0.04, respectively). In cases with high CHFR and CDO1-RMV, the use of postoperative adjuvant chemotherapy (POAC) was related to significantly higher RFS (p = 0.006 and p = 0.001, respectively). However, no significant effect of POAC was seen in high SOX11-RMV cases (p = 0.24). Conclusions: This study demonstrated the clinical utility of ctDNA methylation analysis for predicting prognosis in stage I-III CRCs. Furthermore, the ctDNA methylation status might be a biomarker for identifying the patients who can benefit from POAC.