Abstract
BackgroundAberrant DNA methylation is a critical regulator of gene expression and plays a crucial role in the occurrence, progression, and prognosis of colorectal cancer (CRC). We aimed to identify methylation-driven genes by integrative epigenetic and transcriptomic analysis to predict the prognosis of CRC patients.MethodsMethylation-driven genes were selected for CRC using a MethylMix algorithm and LASSO regression screening strategy, and were further used to construct a prognostic risk-assessment model. The Cancer Genome Atlas (TCGA) database was obtained as the training set for both the screening of methylation-driven genes and the effect of genes signature on CRC prognosis. Then, the prognostic genes signature was validated in three independent expression arrays of CRC data from Gene Expression Omnibus (GEO).ResultsWe identified 143 methylation-driven genes, of which the combination of BATF, PHYHIPL, RBP1, and PNPLA4 expression levels was screened as a better prognostic model with the best area under the curve (AUC) (AUC = 0.876). Compared with patients in the low-risk group, CRC patients in the high-risk group had significantly poorer overall survival in the training set (HR = 2.184, 95% CI: 1.404–3.396, P < 0.001). Similar results were observed in the validation set. Moreover, VanderWeele’s mediation analysis indicated that the effect of methylation on prognosis was mediated by the levels of their expression (HRindirect = 1.473, P = 0.001, Proportion mediated, 69.10%).ConclusionsWe identified a four-gene prognostic signature by integrative analysis and developed a risk-assessment model that is significantly associated with patients’ survival. Methylation-driven genes might be a potential prognostic signature for CRC patients.
Highlights
Colorectal cancer (CRC) is the most common malignant tumor of the digestive system [1]
The clinical information of CRC patients contained a training cohort (N = 367) that was extracted from the The Cancer Genome Atlas (TCGA) database and a validation cohort (N = 355) that was obtained from Gene Expression Omnibus (GEO) datasets (GSE17536, GSE17537, and GSE72970)
By the MethylMix algorithm, we identified 143 methylation-driven genes that were transcriptionally regulated with methylation status
Summary
Colorectal cancer (CRC) is the most common malignant tumor of the digestive system [1]. Recent advances in diagnostic and therapeutic modalities for CRC have greatly improved in survival with early colorectal carcinoma, the 5year overall survival (OS) rates remain low in the late stage of CRC [2, 3]. Nowadays the tumor-nodemetastasis (TNM) staging system is identified as the gold standard to determine the prognosis of CRC patients. Aberrant DNA methylation is a critical regulator of gene expression and plays a crucial role in the occurrence, progression, and prognosis of colorectal cancer (CRC). We aimed to identify methylation-driven genes by integrative epigenetic and transcriptomic analysis to predict the prognosis of CRC patients
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