Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults

Skibola, Christine F.; Smith, Martyn T.; Kane, Eleanor; Roman, Eve; Rollinson, Sara; Cartwright, R. A.; Morgan, Gareth J.

doi:10.1073/pnas.96.22.12810

Cited by 458 publications

(358 citation statements)

References 29 publications

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“…However, the results are greatly inconsistent among various as well as within the same cancer sites. Some of these studies reported that MTHFR 677T allele carriers have reduced risks of colorectal [5][6][7][8][9], leukemia [10][11][12], and lung cancers [29]. In contrast, other studies reported elevated risks of esophageal [17], gastric [18], ovarian [30], cervical [14], bladder [13], colorectal [31,32], and lung cancers [33] for MTHFR 677T allele carriers.…”

Section: Discussionmentioning

confidence: 99%

“…Genotypes with the MTHFR 677T allele have been related to protective effects on colon/rectum cancer [5][6][7][8][9], acute lymphocytic leukemia [10][11][12], and increased cancer risk of the bladder [13], cervix [14], breast [15,16], esophagus [17], and stomach [18]. However, only one epidemiological study estimated the relationship between MTHFR polymorphisms and liver cancer among patients with alcoholic cirrhosis and suggested that the MTHFR 677CC genotype increased the risk of developing HCC among patients with high alcohol consumption [19].…”

Section: Introductionmentioning

confidence: 99%

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Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

Cao

Zhang

et al. 2007

Cancer Causes Control

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Objectives-Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective of this study was to evaluate the effects of polymorphisms of the MTHFR gene on the risk of primary liver cancer and their possible effect modifications on various environmental risk factors.Methods-A population-based case-control study was conducted in Taixing, China. MTHFR C677T and A1298C were assayed by PCR-RFLP techniques.Results-The frequency of MTHFR 677 C/C wild homo-zygotes genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratios (ORs) for the MTHFR 677 C/T and T/T genotype were 1.66(95% CI: 1.06-2.61), 1.21(95% CI: 0.65-2.28) respectively when compared with the MTHFR 677 C/C genotype. Subjects carrying any T genotype have the increased risk of 1.55(95% CI: 1.01-2.40) for development of primary hepatocellular carcinoma. A high degree of linkage disequilibrium was observed between the C677T and A1298C polymorphisms, with the D′ of 0.887 and p < 0.01. The MTHFR 677 any T genotype was suggested to have potentially more than multiplicative interactions with raw water drinking with p-value for adjusted interaction of 0.03. Conclusion-We observed that the MTHFR 677 C/T genotype was associated with an increased risk of primary liver cancer in a Chinese population. The polymorphism of MTHFR 677 might modify the effects of raw water drinking on the risk of primary hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

Cao

Zhang

et al. 2007

Cancer Causes Control

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“…promoter polymorphism) and the SNP G-C within the promoter (Kawakami and Watanabe, 2003;Mandola et al, 2003). Similar methods were used to assess the MTHFR 677 C-T polymorphism (Skibola et al, 1999).…”

Section: Sample Collection and Analysismentioning

confidence: 99%

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

et al. 2006

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A two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m À2 over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35 -82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1 -21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8 -31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2 0 -dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile.

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“…[34][35][36] Higher 5,10-methylene-THF and TS levels associated with these variants were suggested to limit DNA damage by reducing uracil incorporation into DNA, thus explaining the protective role of these variants against leukemia. 35 On the other hand, this might also favor the proliferation of residual malignant clone.…”

Section: Dfs But Not Os)mentioning

confidence: 99%

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

150

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The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR) ¼ 2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR ¼ 2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR ¼ 9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults

Cited by 458 publications

References 29 publications

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

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