The accumulation of various genetic and epigenetic changes in colonic epithelial cells has been identified as one of the fundamental processes that drive the initiation and progression of colorectal cancer (CRC). This study aimed to explore functional genes regulated by DNA methylation and their potential utilization as biomarkers for the prediction of CRC prognoses. Methylation-driven genes (MDGs) were explored by applying the integrative analysis tool (methylmix) to The Cancer Genome Atlas CRC project. The prognostic MDG panel was identified by combining the Cox regression model with the least absolute shrinkage and selection operator regularization. Gene set enrichment analysis was used to determine the pathways associated with the six-MDG panel. Cluster of differentiation 40 (CD40) expression and methylation in CRC samples were validated by using additional datasets from the Gene Expression Omnibus. Methylation-specific PCR and bisulfite sequencing were used to confirm DNA methylation in CRC cell lines. A prognostic MDG panel consisting of six gene members was identified: TMEM88, HOXB2, FGD1, TOGARAM1, ARHGDIB and CD40. The high-risk phenotype classified by the six-MDG panel was associated with cancer-related biological processes, including invasion and metastasis, angiogenesis and the tumor immune microenvironment. The prognostic value of the six-MDG panel was found to be independent of tumor node metastasis stage and, in combination with tumor node metastasis stage and age, could help improve survival prediction. In addition, the expression of CD40 was confirmed to be regulated by promoter region methylation in CRC samples and cell lines. The proposed six-MDG panel represents a promising signature for estimating the prognosis of patients with CRC.
Keywords: DNA methylation; TCGA; colon cancer; epigenetics; integrative analyses; prognosis.
© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.