Polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and thymidylate synthase (TYMS) in multiple myeloma risk.
ABSTRACT We tested whether the polymorphisms of the methylenetetrahydrofolate reductase gene, MTHFR C677T and A1298C, the methionine synthase gene, MTR A2756G, the methionine synthase reductase gene, MTRR A66G, and the thymidylate synthase gene, TYMS 2R-->3R, involved in folate and methionine metabolism, altered the risk for multiple myeloma (MM). Genomic DNA from 123MM patients and 188 controls was analysed by polymerase chain reaction and restriction digestion for the polymorphism analyses. The frequency of the MTR 2756 AG plus GG genotype was higher in patients than in controls (39.8% versus 23.4%, P=0.001). Individual carriers of the variant allele G had a 2.31 (95% CI: 1.38-3.87)-fold increased risk for MM compared with others. In contrast, similar frequencies of the MTHFR, the MTRR and the TYMS genotypes were seen in patients and controls. These results suggest, for the first time, a role for the MTR A2756G polymorphism in MM risk in our country, but should be confirmed by large-scale epidemiological studies with patients and controls age matched.
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ABSTRACT: Thymidylate synthase (TS) is a crucial enzyme in folate metabolism and plays a vital role in DNA synthesis and repair. The most common polymorphism in TS is a unique double (2R) or triple (3R) 28-bp tandem repeat sequence in the enhancer region of the TS gene (TSER). This genetic variation in TSER has been widely investigated and has been implicated as a risk factor for the development of various cancers, including acute lymphoblastic leukemia. It has also been found to influence sensitivity to anti-cancer drugs, such as methotrexate. We evaluated this polymorphism in acute lymphoblastic leukemia patients in the Kashmir population. In order to determine whether a double (2R2R) versus a triple (3R3R) 28-bp tandem repeat in the TSER modulates risk for acute lymphoblastic leukemia, 72 acute lymphoblastic leukemia cases and 144 age and gender matched, unrelated healthy individuals from the Kashmir region of India were evaluated for this polymorphism by PCR and direct sequencing. We found the frequency of the TS 2R allele to be 32.6 and 26.0%, in cases and controls, respectively. The TS 2R/2R genotype was found to be present in 15.27% of the cases and 9.72% of the controls, the 2R/3R variant in 34.72% of the cases and 32.63% of the controls, and the 3R/3R genotype in 50.0% of the cases and 57.63% of the controls. There was a significant association between the TS 2R/2R genotype and gender of acute lymphoblastic leukemia patients with males harboring the 2R/2R genotype exhibiting a higher risk of developing acute lymphoblastic leukemia than females (P = 0.009) We concluded that the TSER polymorphism appears not to be a risk factor for susceptibility to acute lymphoblastic leukemia in the Kashmir population.Genetics and molecular research: GMR 01/2012; 11(2):906-17. · 0.99 Impact Factor
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ABSTRACT: Previous studies on the association of Thymidylate synthase (TYMS) polymorphisms with risk of hematological malignancies have produced conflicting results. The purpose of this meta-analysis was to define the effect of TYMS 5'-untranslated enhanced region (TSER) and 3'-untranslated region (TS3'-UTR) polymorphisms on the risk of hematological malignancies. Seventeen articles were identified as eligible in the case of TSER (2R > 3R) polymorphism (4511 cases and 6113 controls) and seven articles in the case of TS3'-UTR (1494del6) polymorphism (2721 cases and 3761 controls). The overall results suggested that either TSER or TS3'-UTR polymorphism was not associated with the risk of hematological malignancies. In stratified analyses, significantly decreased acute lymphoblastic leukemia (ALL) risk was found in adults (2R/3R vs. 2R/2R: odds ratio [OR] = 0.64, 95% confidence interval [CI]: 0.43-0.97), but increased ALL risk was observed in children (3R/3R vs. 2R/2R: OR = 1.46, 95% CI: 1.03-2.06). Increased non-Hodgkin lymphoma risk was found in the Caucasian population (2R/3R vs. 2R/2R: OR = 1.31, 95% CI: 1.10-1.56). Protective effects of the TS3'-UTR polymorphism (-6 bp/-6 bp) on hematological malignancies were found in a homozygote model and recessive model when the source of controls was stratified as hospital based. In conclusion, the TYMS TSER polymorphism may contribute to a susceptibility to risk of ALL in children and non-Hodgkin lymphoma in Caucasians, but protection from ALL risk in adults. The TS3'-UTR polymorphism (-6 bp/-6 bp) may have a protective effect in hematological malignancies.Leukemia & lymphoma 12/2011; 53(7):1345-51. · 2.61 Impact Factor
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ABSTRACT: Data indicates that genetic factors alone do not account for ovarian tumorigenesis, suggesting that epigenetic status additionally affects this process. Therefore, we assessed the possible contribution of polymorphic variants of genes that may affect DNA methylation to the risk of ovarian cancer incidence in the Polish population. Using PCR-RFLP and HRM analyses, we studied the distribution of BHMT (rs3733890), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394) and TCN2 (rs1801198) genotypes and alleles in patients with ovarian cancer (n = 136) and controls (n = 160). Moreover, using DNA and methylation-specific PCR (MSP) we also determined the methylation of the Cadherin 13 (CDH13) promoter in cancerous tissue from these patients. We did not observe a significant association between all studied gene variants and the incidence of ovarian cancer. The lowest P (trend) = 0.1226 was observed for the MTHFR Ala222Val polymorphism. Moreover, the lowest P = 0.0772 was found in the comparison of MTHFR Ala/Ala versus Val/Val and Val/Ala genotypes in patients and control groups. The multifactor dimensionality reduction analysis also did not indicate a significant interactive genetic effect on ovarian cancer incidence for all analyzed SNPs. However, we observed frequent methylation of the CDH13 promoter in approximately 21% (29/136) patients with ovarian carcinomas. Our results might suggest that the selected polymorphic gene variants may not contribute to ovarian cancer incidence.Molecular Biology Reports 12/2011; 39(5):5553-60. · 2.51 Impact Factor