Abstract
Background: Global DNA methylation has an impact in cancer pathogenesis and progression. This study aimed at investigating the impact of global DNA methylation in treatment outcome of Colorectal Cancer (CRC).Patients and Methods: Global DNA methylation was measured by LC/MS/MS in peripheral blood leucocytes of 102, 48, and 32 Egyptian CRC patients at baseline and after 3 and 6 months of Fluoropyrimidine (FP) therapy respectively, in addition to 32 normal healthy matched in age and sex. The genetic expressions of DNA methyl transferases (DNMTs) were determined and correlated with patients‘ survival using univariate and multivariate methods of analyses.Results: Egyptian CRC patients had significant global hypomethylation of 5mC level and 5mC % with overexpression of DNMT3A and DNMT3B. Significant higher 5mC levels were shown in patients > 45 years, male gender, T2 tumors, stage II, negative lymph nodes, and absence of metastasis. FP therapy significantly reduced DNA methylation particularly in the subgroups of patients with high DNA methylation level at baseline and good prognostic features. After 3 years of follow up, patients with 5mC % > 8.02% had significant poor overall survival (OS) while, significant better event-free survival (EFS) was found in patients with 5mC level > 0.55. High initial CEA level and presence of metastasis were significantly associated with hazards of disease progression and death.Conclusion: Global DNA methylation has a significant impact on the treatment outcome and survival of Egyptian CRC patients treated with FP- based therapy.
Highlights
Global DNA methylation has an impact in cancer pathogenesis and progression
The best characterized epigenetic modification is DNA methylation which is a covalent addition of a methyl group (CH3–), obtained from S- adenosyl methionine to the 5 position of a cytosine base within CG dinucleotides by DNA methyl transferase (DNMT) to form 5-methylcytosine (5mC)
DNMT1, DNMT3A, and DNMT3B have been identified as DNA methylation functional enzymes in eukaryotic cells
Summary
Global DNA methylation has an impact in cancer pathogenesis and progression. This study aimed at investigating the impact of global DNA methylation in treatment outcome of Colorectal Cancer (CRC). The levels of DNMT3B and DNMT3A are often increased in various cancer tissues and cell lines (Okano et al, 1998). They cause hypermethylation of promoter CpG-rich regions in a variety of malignancies (Yun et al, 2012) and repress transcription in either methylation-dependent manner (Linhart et al, 2007; Nosho et al, 2009) or through their histone deacetylase activity (Fuks et al, 2001). DNMT3B has been shown to play a role in leukemia development and maintenance of Leukemia stem cell function (Schulze et al, 2016) Contrary to their canonical de novo methylation role, a series of experiments using DNMT genetic knockout cell lines suggest DNMT1 and DNMT3B cooperate to maintain methylation in human cancers (Rhee et al, 2002)
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