A methylation‐driven gene panel predicts survival in patients with colon cancer

• Published in: FEBS open bio Vol. 11; no. 9; pp. 2490 - 2506
• Main Authors: Peng, Yaojun, Zhao, Jing, Yin, Fan, Sharen, Gaowa, Wu, Qiyan, Chen, Qi, Sun, Xiaoxuan, Yang, Juan, Wang, Huan, Zhang, Dong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.09.2021; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Aged; Angiogenesis; Biomarkers; Biomarkers, Tumor; Bisulfite; CD40 antigen; CD40 Antigens - genetics; Colon cancer; Colonic Neoplasms - diagnosis; Colonic Neoplasms - genetics; Colonic Neoplasms - mortality; Colorectal cancer; Colorectal carcinoma; Computational Biology; Deoxyribonucleic acid; DNA; DNA Methylation; DNA sequencing; Epigenesis, Genetic; Epigenetics; Epigenomics - methods; Epithelial cells; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene set enrichment analysis; Genomes; Genotype & phenotype; Humans; integrative analyses; Kaplan-Meier Estimate; Male; Medical prognosis; Metastases; Metastasis; Microenvironments; Middle Aged; Mortality; Neoplasm Staging; Phenotypes; Prognosis; Promoter Regions, Genetic; Regression analysis; ROC Curve; Survival analysis; TCGA; Tumor necrosis factor-TNF; DNA methylation; prognosis; colon cancer; TCGA; epigenetics; integrative analyses
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13242

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. By applying the methylmix algorithm to The Cancer Genome Atlas colon adenocarcinoma samples, we identified a prognostic methylation‐driven gene panel consisting of six genes (TMEM88, HOXB2, FGD1, TOGARAM1, ARHGDIB and CD40) that we have validated internally. We confirmed that CD40, a promising target for cancer immunotherapy, was regulated by methylation of its promoter region in colon cancer tissues and cell lines.