In addition, a significant anti-correlation between levels of RSPO2 and the methylation status of its promoter was observed in patients who had all three mutations (Fig. 6D), which is in agreement with the worse overall survival of these patients (Fig. 6E, Additional file 15: Table S11), indicating that the epigenetic repression of RSPO2 may be associated with the progression of CRC and is more evident at later stages of the adenoma to carcinoma sequence. This evidence concerns the gene RSPO2 and adenoma.