Abstract
BackgroundThe fatality and recurrence rates of bladder cancer (BC) have progressively increased. DNA methylation is an influential regulator associated with gene transcription in the pathogenesis of BC. We describe a comprehensive epigenetic study performed to analyse DNA methylation-driven genes in BC.MethodsData related to DNA methylation, the gene transcriptome and survival in BC were downloaded from The Cancer Genome Atlas (TCGA). MethylMix was used to detect BC-specific hyper-/hypo-methylated genes. Metascape was used to carry out gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A least absolute shrinkage and selection operator (LASSO)-penalized Cox regression was conducted to identify the characteristic dimension decrease and distinguish prognosis-related methylation-driven genes. Subsequently, we developed a six-gene risk evaluation model and a novel prognosis-related nomogram to predict overall survival (OS). A survival analysis was carried out to explore the individual prognostic significance of the six genes.ResultsIn total, 167 methylation-driven genes were identified. Based on the LASSO Cox regression, six genes, i.e., ARHGDIB, LINC00526, IDH2, ARL14, GSTM2, and LURAP1, were selected for the development of a risk evaluation model. The Kaplan–Meier curve indicated that patients in the low-risk group had considerably better OS (P = 1.679e−05). The area under the curve (AUC) of this model was 0.698 at 3 years of OS. The verification performed in subgroups demonstrated the validity of the model. Then, we designed an OS-associated nomogram that included the risk score and clinical factors. The concordance index of the nomogram was 0.694. The methylation levels of IDH2 and ARL14 were appreciably related to the survival results. In addition, the methylation and gene expression-matched survival analysis revealed that ARHGDIB and ARL14 could be used as independent prognostic indicators. Among the six genes, 6 methylation sites in ARHGDIB, 3 in GSTM2, 1 in ARL14, 2 in LINC00526 and 2 in LURAP1 were meaningfully associated with BC prognosis. In addition, several abnormal methylated sites were identified as linked to gene expression.ConclusionWe discovered differential methylation in BC patients with better and worse survival and provided a risk evaluation model by merging six gene markers with clinical characteristics.
Highlights
The fatality and recurrence rates of bladder cancer (BC) have progressively increased
We found that a high expression and hypomethylation of ARHGDIB and ARL14 were meaningfully correlated with better prognosis (Fig. 7c, d)
Based on public data from the The Cancer Genome Atlas (TCGA) database, we used MethylMix in R and a least absolute shrinkage and selection operator (LASSO) Cox analysis to screen methylation-driven genes associated with prognosis in BC patients
Summary
The fatality and recurrence rates of bladder cancer (BC) have progressively increased. 76,000 new cases and 16,000 deaths are attributed to BC in the USA per year [2]. With such a large patient population, accurately diagnosing and effectively treating BC have become difficult challenges for basic medical researchers and urologists. Aberrant DNA methylation, i.e., hyper- or hypomethylation, on CpG islands of promoters is one such mechanism, resulting in aberrant gene expression and having a major impact on the biological behaviour of BC [4, 5]. Dulaimi et al [8] reported that the detection of hypermethylation in the APC, RASSF1A, and ARF genes in BC patients may act as a non-invasive method for early diagnosis. Ohad et al [10] found that CDH13 is downregulated by promoter methylation in BC patients, and this may be closely associated with tumour development
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