Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K.

Rashidah Baharudin,Azliana Muhamad Yusof,Wan Fahmi Wan Mohamad Nazarie,Learn-Han Lee,Muhiddin Ishak,Sazuita Saidin,Nurul-Syakima Ab Mutalib,Saiful Effendi Syafruddin

doi:10.3390/diagnostics12010198

Abstract

The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.

Highlights

IntroductionIn Malaysia, Colorectal cancer (CRC) is identified as the most common cancer in men and the second most common cancer in women [1]
Colorectal cancer (CRC) is a leading cause of morbidity and cancer death worldwide
The heterogeneity of CRC evolved from multiple pathways, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and CpG Island Methylator Phenotype (CIMP) [2]

Summary

Introduction

In Malaysia, CRC is identified as the most common cancer in men and the second most common cancer in women [1]. This disease is highly heterogeneous, with varying responses to cancer therapy and prognosis. The heterogeneity of CRC evolved from multiple pathways, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and CpG Island Methylator Phenotype (CIMP) [2]. DNA methylation may serve as a potential biomarker for cancer diagnosis, predicting patient prognosis, and monitoring response towards therapy. Several studies have been conducted to identify a methylation biomarker with high specificity and sensitivity to be used in the diagnosis of CRC. A meta-analysis from 38 studies has offered the potential diagnostic markers of hypermethylation SFRP1, SFRP2, NDRG2, and VIM genes in CRC patients [14]

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