Association between the<i>MTHFR</i>A1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children

Ramos, Flávio José da Costa; Muniz, Maria Tereza Cartaxo; Silva, Vanessa Cavalcante; Araújo, Marina Rachel; Leite, Ednalva Pereira; Freitas, Elizabete M.; Zanrosso, Crisiane Wais; Hatagima, Ana; Mello, Maricilda Palandi de; Yunes, José Andrés; Marques-Salles, Terezinha de Jesus; Santos, Neide; Brandalise, Sílvia Regina; Pombo‐de‐Oliveira, Maria S.

doi:10.1080/10428190600800132

Cited by 18 publications

(7 citation statements)

References 16 publications

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“…Various studies described MTHFR genotypes as associated with increased risk of cancers including acute leukemias [16,27,28]; however, other studies [29,30] do not support this suggestion.…”

Section: Discussionmentioning

confidence: 91%

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Tantawy

El-Bostany

Adly

et al. 2010

Blood Coagulation & Fibrinolysis

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Genetic variations of the enzymes involved in chemotherapy metabolism in cancer patients may play a role in determining relapse and toxicity risks. Methotrexate is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5,10 methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is central to folate metabolism and has two common functional polymorphisms (C677>T and A1298>C). The present study aimed to assess the prevalence of MTHFR polymorphisms C677>T and A1298>C in Egyptian children with ALL and the relation to the frequency of drug-induced complications and relapse rate. Forty ALL patients were included in the study. They were treated according to modified ALL-BFM 90 protocol, and were followed up for 3.1-6.5 years. The severity and duration of hepatic, mucosal and infectious complications during therapy were reported. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay. The MTHFR C677>T polymorphic allele frequencies were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively among the studied ALL patients. The MTHFR A1298>C polymorphic allele frequencies were 40, 35, and 25% for AA, AC, and CC genotypes, respectively. Methotrexate therapy was significantly associated with increased grade III/IV toxicity in TT genotype: diarrhea in 81.3%, oral mucositis in 81.3%, elevated transaminases in 87.5%, neutropenia in 78.7% compared to values of 7.7, 7.7, 15.3, and 7.7% in CC genotype, respectively (P < 0.0001, P < 0.0001, P < 0.0001, and P U 0.03). The 677 TT genotype was significantly associated with relapse in 5 years in 56.3%, compared to 18.2% in CT and 0% in CC alleles. The overall 5 years survival was significantly lower in 677 TT (50%) compared with CC genotypes (92.3%) (P U 0.001). No significant relation was found between MTHFR A1298C polymorphism and the risks of therapy induced complications orrelapse rateinthestudied ALLpatients. MTHFR TTgenotype issignificantlyassociated withincreasedmucosalandhepatic toxicity during methotrexate therapy as well as increased relapse rate in childhood ALL. Because of the relatively high prevalence of the TT genotype in the studied Egyptian children with ALL, MTHFR gene polymorphisms should be studied in large multicenter studies; and dosage modification of methotrexate in the ALL treatment protocols should be considered based on the MTHFR gene pattern.

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“…Various studies described MTHFR genotypes as associated with increased risk of cancers including acute leukemias [16,27,28]; however, other studies [29,30] do not support this suggestion.…”

Section: Discussionmentioning

confidence: 91%

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Tantawy

El-Bostany

Adly

et al. 2010

Blood Coagulation & Fibrinolysis

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“…Sample size ranged from 27 to 1,700 (including 1,838 patients with AML and 5,318 healthy controls). Among these, five studies were in Caucasian descent [17], [19]–[22], five studies of Asian descent [14], [18], [23]–[25] and three studies of Brazilian descent [7], [15], [16]. Thirteen studies including 1838 cases and 5318 controls had examined the association of MTHFR C677T polymorphism with AML risk, and 9 studies with a total of 1335 patients and 4295 controls investigated the association between MTHFR A1298C polymorphism and AML risk.…”

Section: Resultsmentioning

confidence: 99%

Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis

Qin

Zhang

et al. 2014

PLoS ONE

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Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98–1.04; 95% CI, 0.86–0.92 to 1.09–1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis.

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“…However, adverse effects like an increased risk of neural tube defects [11], hypertension [32] or acute myeloid leukemia in Brazilian children [33] were also described.…”

Section: Discussionmentioning

confidence: 99%

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

et al. 2011

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BackgroundThe polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G.FindingsHaplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele.ConclusionGiven that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.

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Association between theMTHFRA1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children

Cited by 18 publications

References 16 publications

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

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