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

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.

Rebound increase in microRNA levels at the end of 5-FU-based therapy in colorectal cancer patients

“…The use of 5-FU-based therapy is still the cornerstone in CRC treatment, despite the significant induction of its target, thymidylate synthase (TYMS), after 6 months of its usage, as we recorded before in a previous publication 32 . Digital karyotyping identified amplification of an approximately 100-kb region on chromosome 18p11.32 that contains the coding of TYMS in metastatic CRC patients subjected to prior treatment with 5-FU-based therapy 33 .…”

Intraovarian condensed platelet cytokines for infertility and menopause—Mirage or miracle?

“…One mechanism not yet associated with intraovarian PRP effects is DNA methylation (i.e., epigenetic alterations regulated by DNA methyltransferases). For mammals, this involves covalent transfer of methyl groups from S-adenosyl-1-methionine (SAM) to cytosine within CpG islands (Fouad et al, 2021).…”