Methylation-Based Therapies for Colorectal Cancer

Abstract

Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

Genomic and Metabolomic Landscape of Right-Sided and Left-Sided Colorectal Cancer: Potential Preventive Biomarkers

“…In one study, the incubation of prostate cells with sarcosine stimulated DNA methyltransferases (DNMTs), resulting in increases in global DNA methylation [37]. In another study, aberrant DNMT expression was reported to be associated with CRC and was proposed as a potential therapeutic target [40]. The different levels of sarcosine between patients with LCRC and RCRC may indicate discrepancies in the methylation status of the genome.…”

Distant Metastasis in Colorectal Cancer Patients—Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review

“…Low miR-31-3p expression in patients treated with standard chemotherapy and cetuximab was associated with longer progression-free survival compared to patients expressing high levels of miR-31-3p [ 186 , 187 , 188 , 189 , 190 ]. The CIMP-positive tumors (hypermethylation of at least three out of five pre-defined marker) displayed independent biomarker or recurrence in CRC [ 191 , 192 , 193 , 194 ]. Further studies are urgently needed to identify and validate new biomarkers to improve outcomes in patients with CRC.…”

In silico transcriptomic analysis of ascending colon cancer unearths known and novel genes and gene sets regard to characteristic features of colon cancer

“…[37] Based on the fundamental role of DNA methylation in colon cancer development, the application of DNMT inhibitors for the treatment of colon cancer patients, especially patients with DNA hypermethylation, is recommended as a result of studies. [38] Our results showed that the gene sets of Methyl transferase activity are enriched in ascending colon tumors. This suggests that such agents may be more effective in the treatment of this type of colon cancer subgroups especially.…”