Abstract
AbstractThis study was designed to investigate the influence of TSER and MTHFR polymorphisms on the clinical outcomes of patients with colorectal cancer receiving 5-FU-based chemotherapy. Genomic DNA was isolated from 103 frozen or paraffin-embedded tissues of colorectal cancer patients. The genotypes of two common polymorphisms were determined by PCR-RFLP. Patient prognoses were compared with genotype groups and analyzed according to tumor location. Polymorphisms of TSER and MTHFR 677C>T were not significantly associated with clinicopathological factors. There were no differences in prognosis between genotypes or functional groups when the TSER and MTHFR groups were considered separately. However, analysis of combined genotypes of the TSER and the MTHFR 677C>T polymorphisms were associated with the survival rate of colorectal cancer patients who received 5-FU-based chemotherapy (p=0.028). Prognosis of colorectal cancer patients was significantly different between proximal colon and distal colon cancers (p=0.002). However, prognosis did not receive any effect of the combined genotype when analyzed according to tumor location, such as proximal and distal colon cancer. The combined TSER and MTHFR 677C>T genotypes can be prognostic factors in colorectal cancer, where gene-gene interactions between the genotypes may occur.
Highlights
Despite advancements in the diagnosis and early treatment of colorectal cancer, the need for better tools to predict outcome and response to treatment is well recognized
We investigated the associations between two common polymorphisms and prognosis in 103 colorectal cancer patients receiving 5-FU chemotherapy
We evaluated whether combined genotypes of the Methylenetetrahydrofolate reductase (MTHFR) 677C>T and thymidylate synthase enhance region (TSER) polymorphisms affect colorectal cancer patient survival
Summary
Despite advancements in the diagnosis and early treatment of colorectal cancer, the need for better tools to predict outcome and response to treatment is well recognized. Pharmacogenetics has attracted considerable attention in the study of cancer chemotherapy treatment in recent years. 5-FU has been used in the treatment of cancers such as colorectal cancer, breast cancer and head and neck cancer for about 50 years. The major target of 5-FU is thymidylate synthase (TS), which catalyzes the transformation dUMP into dTMP, an important process in DNA synthesis and repair. Objective tumor responses are observed in only 15% to 20% of patients treated with 5FU.[1] One current strategy to improve the effectiveness of chemotherapy for the treatment of advanced colorectal cancer is based on the ability of reducing folate to modulate the cytotoxic effect of 5-FU. Experimental studies have established that optimal TS inhibition requires the stabilization of ternary complex between TSER, fluorodeoxyuridinemonophosphate (FdUMP) converted from 5-FU, and 5,10- methylenetetrahydrofolate (CH2FH4).[2,3] clinical studies have demonstrated that higher chemotherapy efficacy of 5-FU is associated with folic acid, a precursor of 5,10-methylenetetrahydrofolate.[4,5]
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