In-silico Analysis to Identify Differentially Expressed and Methylated Genes in Esophageal Squamous Cell Carcinoma: Search for Potential Biomarkers

Abstract

Early detection and diagnosis aided by quality treatment and proper patient care is crucial for reducing the overwhelming cancer burden [01]. Esophageal cancer is a highly aggressive cancer in which esophageal epithelial cells grow abnormally into tumor cells, which have the capacity to metastasize in later stages. Esophageal Squamous Cell Carcinoma [ESCC] is associated with high mortality rates, poor prognosis and differences in patient response to specific treatment modalities and metastatic potential. Despite various therapeutic interventions, there have not been any remarkable results in parameters like increase in prognosis, and 5-year survival rates [02-03]. Comprehensive studies focusing on potential molecular mechanisms of ESCC development, progression, and invasion are needed for improvement of the current scenario of diagnosis and treatment.

 New diagnostic biomarkers specific to the stage and patient response will provide significant therapeutic targets for ESCC. This approach will be effective for many patients of ESCC to avoid unnecessary aggressive treatments and it will enable the regime of individualized targeted therapy [04-05]. The development, progression, and metastasis of ESCC is a multi-step process with multiple genes associated with growth, proliferation, invasion, and apoptosis. Multiple genetic alterations have been observed in ESCC which are crucial in tumorigenesis [06]. These alterations and differential changes in gene expression can provide better insights into the molecular mechanism underlying ESCC. Hence, identification of the novel differentially expressed genes in ESCC tumor can reveal underlying mechanisms which are not been fully elucidated till now. Further, functional validation of differentially expressed genes in ESCC which can function as diagnostic markers and therapeutic targets can provide significant improvements in early diagnosis and treatment. Several gene signatures can have a potential prognostic role and clinical outcome [07].

As an epigenetic alteration, DNA methylation affects the expression of genes and has a significant contribution in the onset and progression of cancer [08-09]. Differentially expressed and methylated genes (DEMG’s) have a critical function in the tumorigenesis & etiology of esophageal squamous cell carcinoma. DEMG’s could serve as an important therapeutic target and biomarker for early diagnosis and prognosis in ESCC. Understanding of DNA methylation status in ESCC can provide better insights into molecular mechanisms and pathogenesis of ESCC. Aberrant DNA methylation changes can be used for elucidating markers for early diagnosis, better prognosis, chemoprevention, and personalized therapy [10].

In this study, integrated bioinformatics analysis has been applied to identify differentially expressed and aberrantly methylated genes in ESCC (Fig.1). For insights into molecular mechanisms and pathogenesis of ESCC, notable pathways associated with ESCC were identified (Fig.4). Here, we have 321 upregulated-hypomethylated genes and 562 downregulated-hypermethylated genes were obtained from selected microarray datasets available at Gene Expression Omnibus Database (Fig. 2 & 3). Functional enrichment analysis of these genes disclosed that differential expression and aberrant methylation of genes affects multiple pathways involved in ESCC. Genes with abnormal methylation can be used as non-invasive biomarkers for cancer diagnosis and detection. Investigation of epigenetic changes linked molecular mechanisms in ESCC can provide promising results in early diagnosis and treatment. Findings of this study can provide new insights about ESCC initiation and progression.