[Show abstract][Hide abstract] ABSTRACT: The major targets of 5-fluorouracil (5-FU) are thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR). Therefore, we hypothesized that the variable number of tandem repeat (VNTR) of the thymidylate synthase enhancer region (TSER) together with methylenetetrahydrofolate reductase (MTHFR 677C>T) polymorphism could alter drug activity and predict drug toxicity or efficacy. This 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 samples of colorectal cancer patients. The genotypes of two common polymorphisms (TSER and MTHFR 677C>T) were determined by polymerase chain reaction-restriction fragment length polymorphism. Patient prognoses were compared with genotype groups and analyzed according to tumor location and gender. 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 male group also showed a significant difference between low and high risk types of TSER and MTHFR combined genotypes when stratified according to gender (P=0.019). In conclusion, the combined TSER and MTHFR 677C>T genotypes can be potential prognostic factors in colorectal cancer with 5-FU-based chemotherapy, especially in male gender in Koreans.
[Show abstract][Hide abstract] ABSTRACT: Genetic instability resulting from mutations in repair genes, defects in folic acid metabolism or DNA synthesis has been reported to contribute significantly to the development of skin cancer. The enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are essential participants in folic acid metabolism and DNA synthesis. Thus, the present case-control study was conducted to determine whether an association exists between the MTHFR/TS polymorphisms and squamous cell carcinoma (SCC) and/or basal cell carcinoma (BCC) among Korean individuals. The study subjects comprised 95 patients with SCC, 100 patients with BCC and 207 controls with no evidence of malignancy or pre-malignant lesions. Patients with skin cancer and control samples were analyzed for polymorphisms of the MTHFR or TS genes by means of polymerase chain reaction-restriction fragment length polymorphism. The MTHFR 677C>T and MTHFR 1298A>C polymorphisms showed no significance with regard to the development of SCC and BCC. However, within the 6 bp insertion (ins)/deletion (del) polymorphism in the 3'-untranslated region (3'-UTR) of the TS gene, the BCC group showed statistical significance with a 2.8-fold increased risk of cancer development [adjusted odds ratio (AOR)=2.821] in heterozygous mutations (0 bp/6 bp), 7.5-fold (AOR=7.539) in homozygous mutations (6 bp/6 bp) and 3-fold (AOR=3.079) upon combination of heterozygous mutations and homozygous mutations (0 bp/6 bp + 6 bp/6 bp). We thus conclude that the 6 bp ins/del polymorphism in the 3'-UTR is associated with increased risk of the development of skin cancer among Korean individuals with BCC.
Full-text · Article · Sep 2010 · Molecular Medicine Reports
[Show abstract][Hide abstract] ABSTRACT: Thymidylate synthase (TS) plays an important role in the conversion of dUMP to dTMP. Polymorphisms of the TS gene affect the expression of the gene, which in turn may result in differences in the outcome of cancer chemotherapy and the progression of gastric cancer.
These types of TS polymorphism were investigated in 318 gastric cancer patients and 280 controls. A variable number of tandem repeats (VNTR; 2R or 3R) in the thymidylate synthase enhancer region (TSER), a G/C single nucleotide polymorphism within the second repeat sequence of 3R (3G or 3C), and a 6 bp insertion/deletion polymorphism (6 bp or 0 bp) in the TS 3'-untranslated region (3'-UTR) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients were sub-grouped by the Lauren classification.
The TSER 2R/2R genotype had a high odds ratio in gastric cancer and for the intestinal type, but was not statistically significant (adjusted odds ratio, AOR=2.31, 95% confidence interval, CI=0.94-5.65; and AOR=2.53, 95% CI=0.98-6.54, respectively). Among the combined genotypes of TSER VNTR-3'-UTR 6 bp ins/del, 2R2R-6 bp/6 bp having 4 risk alleles conferred a significantly high risk of gastric cancer, particularly of the intestinal type (AOR=8.70, 95% CI=1.09-68.93; and AOR=10.86, 95% CI=1.32-89.09, respectively).
Our results indicate that the 2R/2R-6 bp/6 bp combined genotype may be related to high gastric cancer susceptibility.
Full-text · Article · Jun 2010 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Genetic instability resulting from mutations in repair genes or denaturation in DNA synthesis has been reported to play an
important role in the development of cancer. Through studies of single nucleotide polymorphisms (SNPs), X-ray repair cross-complementing
groups 1 (XRCC1), which is an enzyme involved in the process of base repair, has been reported to be linked to the development of cancer.
Recently, their roles in other causes of morbidity have also attracted considerable interest. Thus the present case-control
study was conducted to determine the possibility of an association betweenXRCC1 polymorphisms and stomach cancer among Korean subjects. The study subjects were composed of 187 patients with stomach cancer,
and 206 control subjects with no evidence of any malignancy or premalignant lesions. All the subjects were analyzed for polymorphisms
of theXRCC1 gene by means of polymerase chain reaction-restriction fragment length polymorphism.XRCC1 Arg l94Trp(C>T), Arg280His(G>A) and Arg399Gln(G>A) polymorphism. showed no significant link to the development of stomach
cancer. Heterozygous mutations ofXRCC1 Argl94Trp (C>T) and Arg280His(G>A) polyroorphisms, bowever, shewed the tendency to be linked to an increased development
of intestinal cancer. The haplotypes ofXRCC1 Arg l94Trp(C>T), Arg280His(G>A) and Arg399Gln(G>A) poIymorphisms were associated with an increased risk of development of
stomach cancer among individuals with intestinal and diffuse types. We thus conclude that the haplotypes ofXRCC1 polymorphisms are associated with an increased risk of development of stomach cancer.
[Show abstract][Hide abstract] ABSTRACT: 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation; thymidylate synthase (TS) is a rate-limiting enzyme in the synthesis of dTMP and DNA repair. The clinical role of genetic polymorphisms of MTHFR and that of the TS enhancer region (TSER) were demonstrated in several clinical studies with colorectal, esophageal, gastric and breast cancer. However, there have never been any studies on the association between cholangiocarcinoma (CCC) and genetic polymorphisms of MTHFR and TSER. Therefore, the polymorphism of MTHFR and TSER, which share a common substrate, 5,10-methylenetetrahydrofolate, in CCC was examined, concurrently. The influence of these polymorphisms on plasma homocysteine levels was also investigated.
Blood samples were obtained from 47 patients with CCC and 204 healthy control donors. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), the C to T transition at position 677 of MTHFR and tandem repeat of 28bp in the enhancer region of TS gene were analyzed. Plasma homocysteine levels were also determined.
According to the logistic regression model, a combination of MTHFR 677CC with the TSER 2R(+) genotype had a relative risk of 5.38 (95% CI, 1.23-23.56) of developing CCC compared to MTHFR 677CC with TSER 2R(-) (p = 0.0257). The level of homocysteine was lower in CCC patients than healthy controls without statistical significance (8.27 +/- 4.17 vs. 9.40 +/- 2.57, p = 0.093).
Our data suggest a role of MTHFR 677CC with the TSER 2R(+) genotype in increasing the risk of CCC. This study is the first to suggest an association between CCC and the polymorphisms of MTHFR and TSER.
Full-text · Article · Nov 2006 · Anticancer research