The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

Mariam Ahmed Fouad; Salem Eid Salem; Marwa M Hussien; Doaa Mohamed Badr; Abdelrahman N Zekri; Hafez Farouk Hafez; Samia A Shouman

doi:10.1177/2516865720986231

The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

Epigenet Insights. 2021 Feb 14:14:2516865720986231. doi: 10.1177/2516865720986231. eCollection 2021.

Authors

Mariam Ahmed Fouad¹, Salem Eid Salem², Marwa M Hussien², Doaa Mohamed Badr¹, Abdelrahman N Zekri³, Hafez Farouk Hafez¹, Samia A Shouman¹

Affiliations

¹ Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Egypt.
² Medical Oncology Department, National Cancer Institute, Cairo University, Egypt.
³ Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Egypt.

Abstract

Aims: This study investigated the impact of promoter methylation of flouropyrimidine (FP) metabolizing and cyclooxygenase 2 (COX2) genes on their mRNA expression and on the clinical outcome of colorectal cancer (CRC) patients.

Methods: Methylation specific-PCR and real time-PCR of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and COX2 were performed at baseline and after 3 and 6 months of FP therapy. Pairwise comparisons were conducted between the subgroups of CRC patients. The event free survival (EFS) and the hazard of progression were estimated by univariate and multivariate analyses.

Results: At baseline CRC patients, both TS and TP were overexpressed, in spite of the unmethylation of TS and the full methylation of TP genes. Significant downexpression of DPD and COX2 were associated their promoter's methylation. At the end of FP therapy, TS, DPD and COX2 were overexpressed by 7.52, 2.88 and 3.45 folds, respectively, while TP was downexpressed by 0.54 fold. However, no change was observed in the methylation status of genes with FP therapy. Pairwise comparisons revealed significant difference in the expression and the methylation status of genes according to the clinicopathological characters of CRC patients either at baseline or after FP therapy. The overexpression of DPD and COX2 genes were indicators for a poor EFS of CRC patients. Also, the high level of COX2 expression was found to be significantly correlated with the hazard of progression (HR = 1.73, 95% CI = 1.02-3.03).

Conclusion: The promoter methylation of FP metabolizing and COX2 genes has significant impact on the expression and the treatment outcome of CRC patients.

Keywords: Colorectal cancer; cyclooxygenase 2; fluoropyrimidine metabolizing; gene expression; promoter methylation; survival and progression.